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CDK9-55 guides the anaphase-promoting complex/cyclosome (APC/C) in choosing the DNA repair pathway by affecting the UFL1 ubiquitination.

ABSTRACT: DNA double-strand breaks (DSBs) contribute to genome instability, a key feature of cancer. DSBs are mainly repaired by homologous recombination (HR) and non-homologous end-joining (NHEJ). We investigated the role of an isoform of the multifunctional cyclin-dependent kinase 9, CDK9-55, in DNA repair, by generating CDK9-55-knockout HeLa clones (through CRISPR-36 Cas9), which showed potential HR dysfunction. A phosphoproteomic screening in these clones treated with camptothecin revealed that CDC23 (cell division cycle 23), a component of the E3 ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome), is a new substrate of CDK9-55, with S588 being its putative phosphorylation site. Mutated non-phosphorylatable CDC23(S588A) affected the repair pathway choice by impairing HR and favouring error prone NHEJ. Moreover, CDC23(S588A) promoted the ubiquitination of UFL1, a recently identified HR player. Overall, CDK9-55 could guide APC/C in choosing the correct DNA repair pathway, possibly by regulating UFL1 stability. This CDK9 role should be considered when designing CDK-inhibitor-based cancer therapies.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Antonio Giordano

PROVIDER: MSV000087856 | MassIVE | Tue Jul 20 08:53:00 BST 2021

SECONDARY ACCESSION(S): PXD027441

REPOSITORIES: MassIVE

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ASF1 acts with RIF1 to promote DNA end-joining in BRCA1 deficient cells

Project description:RIF1 acts downstream of 53BP1 to coordinate DNA double strand break repair pathway choice between non-homologous end joining (NHEJ) and homologous recombination (HR). Here we identified ASF1 as an endogenous RIF1-associated protein. We showed that ASF1 forms complex with RIF1 and regulates RIF1-dependent functions in DNA damage response.

2022-06-09 | PXD027727 | Pride

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Project description:Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage responsefactor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice, and rescues HR deficiency, as measured by hypersensitivity to PARP (polyADPribose polymerase) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA cross-link repair that is distinct from HR. Disruption of the non-homologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi Anemia pathway for ICL repair. Brca1 therefore has two separate roles in ICL repair, whereas FANCD2 provides a key activity that can not be bypassed by ablation of 53BP1 or Ku.

2012-09-30 | GSE35698 | GEO

BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair

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2014-03-23 | E-MTAB-1241 | biostudies-arrayexpress

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2024-02-15 | PXD042607 | Pride

CTCF cooperates with CtIP to drive homologous recombination repair of double-strand breaks

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ATM Inhibition Exploits Checkpoint Defects and ATM-Dependent Double Strand Break Repair in TP53-Mutant Glioblastoma

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2024-03-08 | PXD047837 | Pride

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2017-07-26 | GSE84610 | GEO

NFKB2 Knockdown Reduces Expression of HR-Related Genes

Project description:Homologous recombination (HR) serves multiple roles in DNA repair that are essential for maintaining genomic stability. The central HR protein, RAD51, is frequently overexpressed in human malignancies, thereby elevating HR proficiency and promoting resistance to DNA-damaging therapies. Here we find that non-canonical NF-κB factors control the expression of RAD51 andother HR-promoting proteins. Transcriptional silencing of p100/p52 reduces RAD51 protein levels in multiple human cancer subtypes. RNA-seq after p100/p52 silencing identifies RAD51 as the most differentially expressed gene among 40 genes with known relevance to HR. While p100/p52 depletion inhibits HR function in human tumor cells, it does not influence the function of other double-strand DNA repair pathways including single-strand annealing, microhomology mediated annealing, or non-homologous end joining.

2022-06-07 | GSE148511 | GEO

High-throughput capture of cis-rearrangement and trans-rearrangement sequence [LAM-HTGTS]

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