DNA Repair Genes in Cancer and Inherited Disease

Helps coordinate homologous recombination at DNA double-strand breaks with PALB2, BRCA2 and RAD51. Harmful germline or tumour changes can create homologous-recombination deficiency, but PARP-inhibitor evidence and approval language remain cancer- and regimen-specific.

The primary double-strand break sensor kinase, activated by the MRN complex and initiating a phosphorylation cascade that coordinates HR repair, cell cycle checkpoints, and apoptosis. Loss causes ataxia-telangiectasia with extreme radiosensitivity.

Beyond its lipid phosphatase role, PTEN localises to the nucleus where it contributes to chromosomal stability and DNA double-strand break repair by facilitating RAD51 retention. Nuclear PTEN loss is associated with genomic instability independent of AKT.

Core component of the MutLα mismatch repair complex that corrects base mismatches and small insertion/deletion loops from replication slippage. Biallelic loss causes microsatellite instability (MSI-high), a biomarker for PD-1 checkpoint inhibitor sensitivity.

CHK2 kinase activated by ATM that reinforces the DNA damage checkpoint through p53 Ser20 phosphorylation and BRCA1 activation. Moderate cancer predisposition gene; CHEK2 1100delC variant is a recurrent breast cancer risk allele.

p14ARF encoded by CDKN2A sequesters MDM2 in the nucleolus in response to oncogenic signalling, stabilising p53 for apoptosis or senescence induction. This positions CDKN2A as a link between replication stress, p53 activation, and the DNA damage response.

mTORC1 activity coordinates the cellular response to DNA damage by modulating cap-dependent translation; excessive mTOR activity can override DNA damage-induced translation suppression, reducing repair efficiency and promoting genomic instability in some contexts.

Hypoxia via HIF-1α suppresses expression of key DNA repair factors including BRCA1, RAD51, and MLH1, creating transient BRCAness and microsatellite instability in hypoxic tumour regions — a mechanistic link between tumour microenvironment and mutational heterogeneity.

Transcriptionally activates DNA repair genes including DDB2 (NER) and XPC following UV damage, and GADD45 for global genome repair. p53's ability to pause the cell cycle until repair is complete is as important as its apoptotic function for maintaining genome integrity.