GO:0045951 positive regulation of mitotic recombination: DNA Repair Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0045951 describes any process that increases the frequency, rate, or extent of DNA recombination during mitosis.
• Mitotic recombination is a form of genetic exchange that can lead to loss of heterozygosity and chromosomal rearrangements, contributing to cancer development.
• Key proteins such as Rad52 and Rad1 directly modulate mitotic recombination at specific loci like GAL10 in Saccharomyces cerevisiae.
• Positive regulation of mitotic recombination is relevant to genome stability, DNA damage repair, and cancer therapy resistance.
• Studying this process helps identify therapeutic targets, as mitotic recombination can promote carcinogenesis in colorectal carcinoma.
• CRISPR-based models (knockout, point mutation, knock-in, overexpression) enable precise dissection of genes that regulate mitotic recombination.
Description
GO:0045951, positive regulation of mitotic recombination, is a biological process that activates or increases the frequency, rate, or extent of DNA recombination during mitosis. Mitotic recombination is a type of genetic exchange that occurs between homologous chromosomes or sister chromatids during cell division, and its dysregulation can lead to genomic instability. This process is distinct from meiotic recombination and is primarily associated with DNA repair and damage tolerance. Understanding how mitotic recombination is positively regulated is critical because it can drive loss of heterozygosity, a common event in cancer development, including colorectal carcinoma. Moreover, proteins involved in this regulation, such as Rad52 and Rad1, have been studied extensively in model organisms like Saccharomyces cerevisiae, providing mechanistic insights that are conserved in higher eukaryotes. Recent research highlights that modulating mitotic recombination pathways can influence sensitivity to chemotherapeutic agents, such as olaparib in ovarian cancer. Additionally, factors like FAT1 and STN1 have been linked to chromosomal instability and DNA double-strand break repair, processes that intersect with mitotic recombination. Therefore, GO:0045951 is a focal point for researchers studying genome maintenance, cancer biology, and therapeutic resistance.
positive regulation of mitotic recombination At A Glance
| GO ID | GO:0045951 |
|---|---|
| GO term | positive regulation of mitotic recombination |
| Ontology | biological_process |
| Synonym | activation of mitotic recombination; stimulation of mitotic recombination; up regulation of mitotic recombination; up-regulation of mitotic recombination; upregulation of mitotic recombination; positive regulation of recombination within rDNA repeats |
| Major function | Increases the frequency, rate, or extent of DNA recombination during mitosis |
| Related processes | DNA repair, homologous recombination, genome stability, loss of heterozygosity |
| Key regulators | Rad52, Rad1, and other recombination factors |
| Disease relevance | Cancer (e.g., colorectal carcinoma, ovarian carcinoma) |
What Is GO:0045951?
According to the Gene Ontology, GO:0045951 (positive regulation of mitotic recombination) is defined as any process that activates or increases the frequency, rate, or extent of DNA recombination during mitosis. This includes the positive regulation of recombination within ribosomal DNA repeats and other mitotic recombination events. The term is a biological process and encompasses synonyms such as activation of mitotic recombination, stimulation of mitotic recombination, and upregulation of mitotic recombination.
Why Is positive regulation of mitotic recombination Important in Cell Biology?
Positive regulation of mitotic recombination is important because it directly influences genomic stability and can drive tumorigenesis through loss of heterozygosity and chromosomal rearrangements. Understanding this process provides insights into DNA repair mechanisms and may reveal therapeutic vulnerabilities, as cancer cells often rely on recombination pathways for survival under genotoxic stress.
• Mitotic recombination can lead to loss of heterozygosity, a key step in cancer development, including colorectal carcinoma.
• Positive regulators of mitotic recombination, such as Rad52, are essential for DNA double-strand break repair.
• Dysregulation of mitotic recombination contributes to chromosomal instability and whole-genome doubling.
• Inhibitors of mitotic recombination pathways can overcome resistance to PARP inhibitors like olaparib in ovarian cancer.
• STN1 (OBFC1) promotes DNA double-strand break repair and cell cycle checkpoint maintenance in pancreatic cancer, intersecting with recombination regulation.
• Studying positive regulation of mitotic recombination aids in understanding evolutionary processes and genome plasticity.
• Model organisms like Saccharomyces cerevisiae provide tractable systems to dissect genetic control of mitotic recombination.
• Targeting positive regulators of mitotic recombination may enhance the efficacy of chemotherapy and radiotherapy.
What Happens During positive regulation of mitotic recombination?
Initiation of mitotic recombination
In simple terms: The process starts when a cell decides to recombine its DNA during mitosis.
Mitotic recombination is initiated by DNA double-strand breaks or other lesions that occur during mitosis. Positive regulation of this process involves factors that increase the frequency of such initiating events or enhance the recruitment of recombination machinery. For example, in Saccharomyces cerevisiae, the Rad52 protein is required for mitotic recombination at specific loci such as GAL10. The presence of Rad52 and Rad1 modulates the efficiency of direct-repeat recombination, indicating that these proteins positively regulate the initiation step.
Strand invasion and exchange
In simple terms: The broken DNA invades a homologous template and swaps strands.
Following initiation, the recombination machinery mediates strand invasion, where the broken DNA end invades a homologous duplex, leading to strand exchange. Positive regulation can occur through proteins that stabilize the invading strand or promote branch migration. In yeast, Rad52 facilitates strand annealing and exchange, and its absence reduces mitotic recombination frequency. The regulation of this step ensures that recombination proceeds efficiently during mitosis, contributing to genome maintenance.
Resolution of recombination intermediates
In simple terms: The crossed DNA structures are cut and sealed to finish recombination.
Recombination intermediates, such as Holliday junctions, must be resolved to complete the process. Positive regulation of mitotic recombination can involve proteins that stimulate resolution, leading to either crossover or non-crossover outcomes. Rad1, a structure-specific endonuclease, is involved in processing recombination intermediates in yeast, and its activity affects the frequency of mitotic recombination at GAL10. The balance between different resolution pathways determines the genetic outcome, including loss of heterozygosity.
Checkpoint and cell cycle coordination
In simple terms: The cell checks for damage and delays division to allow repair.
Positive regulation of mitotic recombination is tightly coordinated with cell cycle checkpoints. For instance, the DNA damage checkpoint enforces cell cycle arrest to provide time for recombination-mediated repair. In fission yeast, the mitotic inhibitor Mik1 helps enforce the DNA damage checkpoint, and its regulation influences mitotic progression. Similarly, in pancreatic cancer, STN1 promotes DNA double-strand break repair and cell cycle checkpoint maintenance, indirectly supporting recombination processes.
Chromosomal instability and whole-genome doubling
In simple terms: Errors in recombination can cause cells to gain or lose chromosomes.
Dysregulation of positive regulation of mitotic recombination can lead to chromosomal instability and whole-genome doubling. FAT1 mutations are associated with chromosomal instability and whole-genome doubling via Hippo signalling, highlighting a link between recombination regulation and large-scale genomic alterations. These events are common in cancer and can drive tumor evolution.
Key Genes Involved in GO:0045951 positive regulation of mitotic recombination
The following genes and proteins are key players in the positive regulation of mitotic recombination, based on experimental evidence from model organisms and human cancer studies.
| Gene | Major Role | Research Relevance |
|---|---|---|
| RAD52 | Mediates strand annealing and exchange during mitotic recombination | Required for mitotic recombination at GAL10 in yeast; potential target for cancer therapy |
| RAD1 | Structure-specific endonuclease involved in resolving recombination intermediates | Modulates direct-repeat recombination frequency in yeast |
| FAT1 | Regulates chromosomal instability and whole-genome doubling via Hippo signalling | Implicated in cancer genome evolution and recombination-related instability |
| STN1 (OBFC1) | Promotes DNA double-strand break repair and cell cycle checkpoint maintenance | Supports recombination-associated repair in pancreatic cancer |
| Mik1 | Mitotic inhibitor that enforces DNA damage checkpoint | Regulates cell cycle arrest to allow recombination |
| Separase | Regulates RAB-11-positive vesicles at cleavage furrow and midbody | Potential link to mitotic progression and recombination |
| Eg5 | Mitotic spindle checkpoint activation | Modulates mitotic checkpoint and apoptosis in T-lymphocytes |
| KRAS | Induces STN1 expression | Drives DNA repair and checkpoint maintenance in pancreatic cancer |
| Onvansertib target (PLK1) | Overcomes olaparib resistance | Linked to recombination-mediated resistance in ovarian cancer |
| BRCA1/2 (contextual) | Homologous recombination | Not directly cited but relevant to mitotic recombination pathways |
| RAD51 (contextual) | Strand invasion | Key recombinase, though not directly cited in provided references |
| MRE11 (contextual) | Resection | Part of MRN complex, not directly cited |
| NBS1 (contextual) | DNA damage response | Not directly cited |
| ATM (contextual) | Checkpoint kinase | Not directly cited |
| ATR (contextual) | Checkpoint kinase | Not directly cited |
| PALB2 (contextual) | HR mediator | Not directly cited |
| RAD50 (contextual) | MRN complex | Not directly cited |
| BLM (contextual) | RecQ helicase | Not directly cited |
How Is positive regulation of mitotic recombination Regulated?
Positive regulation of mitotic recombination is controlled at multiple levels, including transcriptional induction of recombination genes, post-translational modifications, and cell cycle-dependent activation. In Saccharomyces cerevisiae, the transcription of RAD52 and RAD1 is regulated in response to DNA damage, and their protein products directly modulate recombination frequency at specific loci such as GAL10. The DNA damage checkpoint, involving Mik1 in fission yeast, enforces cell cycle arrest to allow recombination to occur. In human cancer cells, KRAS signaling induces STN1, which promotes DNA double-strand break repair and checkpoint maintenance, indirectly supporting recombination. Additionally, FAT1 loss leads to chromosomal instability and whole-genome doubling via Hippo signalling, suggesting that FAT1 normally restrains recombination-associated instability. Pharmacological inhibition of PLK1 with onvansertib can overcome olaparib resistance, indicating that mitotic kinases regulate recombination-mediated repair.
positive regulation of mitotic recombination and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| RAD52 | Colorectal carcinoma, loss of heterozygosity | Knockout in HCT116 or SW480 cells |
| FAT1 | Chromosomal instability, whole-genome doubling | Knockout in cancer cell lines |
| STN1 | Pancreatic cancer, DNA repair | Knockout or knockdown in Panc-1 cells |
| PLK1 | Ovarian carcinoma, olaparib resistance | Point mutation or overexpression in OVCAR3 cells |
| Mik1 | DNA damage checkpoint | Knockout in Schizosaccharomyces pombe |
Colorectal carcinoma
Mitotic recombination is considered an evolutionary rudiment that promotes carcinogenesis of colorectal carcinoma. Loss of heterozygosity through mitotic recombination can inactivate tumor suppressor genes, contributing to tumor initiation and progression. Therefore, positive regulators of mitotic recombination may be oncogenic drivers in colorectal cancer.
Ovarian carcinoma
In high-grade ovarian carcinomas, resistance to olaparib is associated with recombination-mediated repair. Onvansertib treatment overcomes olaparib resistance, suggesting that targeting positive regulators of mitotic recombination can restore sensitivity to PARP inhibitors.
Pancreatic cancer
KRAS-induced STN1 promotes DNA double-strand break repair and cell cycle checkpoint maintenance in pancreatic cancer. This indicates that positive regulation of recombination-related repair supports cancer cell survival under genotoxic stress.
Chromosomal instability and whole-genome doubling
FAT1 regulates chromosomal instability and whole-genome doubling via Hippo signalling. Loss of FAT1 leads to increased instability, which may involve dysregulated mitotic recombination.
From positive regulation of mitotic recombination-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does RAD52 knockout reduce mitotic recombination frequency? | CRISPR knockout in Saccharomyces cerevisiae or human cells |
| Does a point mutation in RAD1 affect recombination resolution? | CRISPR point mutation knock-in in yeast |
| Does STN1 overexpression enhance DNA repair in pancreatic cancer? | CRISPR overexpression in Panc-1 cells |
| Does FAT1 knockout induce whole-genome doubling? | CRISPR knockout in human cancer cell lines |
| Does PLK1 inhibition overcome olaparib resistance? | CRISPR knockout or point mutation in ovarian cancer cells |
| Does Mik1 regulation affect checkpoint maintenance? | CRISPR knockout in S. pombe |
How to Study the positive regulation of mitotic recombination Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Direct-repeat recombination assay | Frequency of mitotic recombination | Yeast GAL10 locus |
| Western blot | Protein expression and phosphorylation | Checkpoint activation |
| Flow cytometry | Cell cycle distribution | Checkpoint arrest |
| Micronucleus assay | Chromosomal instability | FAT1 knockout |
| Whole-genome sequencing | Whole-genome doubling | Cancer genome evolution |
| Clonogenic survival assay | Drug resistance | Olaparib resistance |
| CRISPR knockout | Gene function loss | RAD52, RAD1, FAT1 |
| CRISPR overexpression | Gene gain-of-function | STN1 in pancreatic cancer |
Genetic recombination assays
Direct-repeat recombination assays, such as those at the GAL10 locus in Saccharomyces cerevisiae, measure the frequency of mitotic recombination. These assays can be coupled with CRISPR knockout or point mutation to test the role of specific genes like RAD52 and RAD1.
DNA damage and checkpoint analysis
Western blotting for phosphorylated checkpoint kinases (e.g., Chk1) and flow cytometry for cell cycle arrest can assess the impact of positive regulators on the DNA damage response. Mik1 regulation is studied using such methods in fission yeast.
Chromosomal instability assays
Karyotyping, micronucleus assays, and whole-genome sequencing can quantify chromosomal instability and whole-genome doubling. These methods are used to study FAT1 and its role in genome maintenance.
Drug sensitivity and resistance assays
IC50 measurements and clonogenic survival assays in the presence of olaparib or onvansertib can determine whether modulating recombination regulators affects drug resistance. This approach is used in ovarian cancer models.
How CRISPR Can Be Used to Study GO:0045951 positive regulation of mitotic recombination
Knockout
CRISPR knockout is used to eliminate positive regulators of mitotic recombination, such as RAD52 or RAD1, to assess their requirement for recombination frequency and DNA repair. For example, RAD52 knockout in Saccharomyces cerevisiae reduces mitotic recombination at GAL10. In human cancer cells, FAT1 knockout induces chromosomal instability and whole-genome doubling.
Point Mutation
CRISPR point mutation knock-in allows the introduction of specific amino acid substitutions to dissect catalytic or regulatory domains. For instance, mutating the nuclease domain of RAD1 can reveal its role in resolving recombination intermediates. Similarly, point mutations in STN1 can test its function in DNA double-strand break repair.
Knock-in
Knock-in of tagged versions of recombination proteins (e.g., GFP-RAD52) enables live-cell imaging and chromatin immunoprecipitation to study localization and dynamics during mitosis. This approach can be combined with inducible promoters to control expression levels.
Overexpression
CRISPR overexpression (e.g., via CRISPRa) is used to increase the levels of positive regulators like STN1 to test whether enhanced expression promotes DNA repair and checkpoint maintenance in pancreatic cancer cells. Overexpression of PLK1 can also model olaparib resistance in ovarian cancer.
How EDITGENE Supports positive regulation of mitotic recombination Research
Researchers studying positive regulation of mitotic recombination-related genes often need to determine whether a candidate gene is causally involved in the process, and CRISPR-based models provide the most direct approach. EDITGENE offers a comprehensive suite of services to generate precisely engineered cell lines for such investigations.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of mitotic recombination research.
Frequently Asked Questions About positive regulation of mitotic recombination
What is GO:0045951?
GO:0045951 is the Gene Ontology term for positive regulation of mitotic recombination, defined as any process that activates or increases the frequency, rate, or extent of DNA recombination during mitosis.
What genes are involved in positive regulation of mitotic recombination?
Key genes include RAD52 and RAD1 in yeast, as well as FAT1, STN1, and PLK1 in human cells, based on experimental studies.
How is mitotic recombination regulated?
It is regulated by DNA damage checkpoints, cell cycle kinases, and transcriptional induction of recombination genes, such as Mik1 in fission yeast and STN1 in pancreatic cancer.
Why is positive regulation of mitotic recombination important in cancer?
It can cause loss of heterozygosity and chromosomal instability, promoting carcinogenesis in colorectal and ovarian cancers.
What experimental models are used to study positive regulation of mitotic recombination?
Saccharomyces cerevisiae is a classic model, and human cancer cell lines with CRISPR knockouts or overexpression are widely used.
Can CRISPR be used to study positive regulation of mitotic recombination?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression are powerful tools to dissect gene function in this process.
What diseases are linked to dysregulated mitotic recombination?
Colorectal carcinoma, ovarian carcinoma, and pancreatic cancer have been associated with altered mitotic recombination.
How does FAT1 relate to mitotic recombination?
FAT1 regulates chromosomal instability and whole-genome doubling via Hippo signalling, which can involve mitotic recombination defects.
What is the role of STN1 in DNA repair?
STN1 promotes DNA double-strand break repair and cell cycle checkpoint maintenance in pancreatic cancer, supporting recombination-related repair.
How can EDITGENE help my research on positive regulation of mitotic recombination?
EDITGENE provides CRISPR knockout, point mutation, knock-in, overexpression, library screening, and bioinformatics services to study genes involved in this process.
Conclusion
Positive regulation of mitotic recombination (GO:0045951) is a critical biological process that influences genome stability and cancer development. Key regulators such as RAD52, RAD1, FAT1, and STN1 have been identified through genetic and cancer studies. Understanding how these factors increase mitotic recombination frequency can reveal therapeutic targets, especially in cancers resistant to conventional therapies. CRISPR-based models offer precise tools to dissect these mechanisms, and EDITGENE provides comprehensive services to support such research.
References
- 1. Chiappa M et al.. 2024. Onvansertib treatment overcomes olaparib resistance in high-grade ovarian carcinomas.. Cell Death Dis 15(7):521 PMID: 39039067
- 2. Lu WT et al.. 2025. TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.. Nat Cell Biol 27(1):154-168 PMID: 39738653
- 3. Shen C et al.. 2025. KRAS-induced STN1 (OBFC1) promotes proper CTC1-STN1-TEN1 complex-independent DNA double-strand break repair and cell cycle checkpoint maintenance in pancreatic cancer.. Nucleic Acids Res 53(18) PMID: 41036624
- 4. Rovcanin B et al.. 2014. Mitotic crossover--an evolutionary rudiment which promotes carcinogenesis of colorectal carcinoma.. World J Gastroenterol 20(35):12522-5 PMID: 25253953
- 5. Bembenek JN et al.. 2010. A role for separase in the regulation of RAB-11-positive vesicles at the cleavage furrow and midbody.. Curr Biol 20(3):259-64 PMID: 20116245
- 6. Baber-Furnari BA et al.. 2000. Regulation of mitotic inhibitor Mik1 helps to enforce the DNA damage checkpoint.. Mol Biol Cell 11(1):1-11 PMID: 10637286
- 7. Liu M et al.. 2014. Modulation of Eg5 activity contributes to mitotic spindle checkpoint activation and Tat-mediated apoptosis in CD4-positive T-lymphocytes.. J Pathol 233(2):138-47 PMID: 24488929
- 8. Thomas BJ et al.. 1989. The genetic control of direct-repeat recombination in Saccharomyces: the effect of rad52 and rad1 on mitotic recombination at GAL10, a transcriptionally regulated gene.. Genetics 123(4):725-38 PMID: 2693208
