DNA is prone to damage from a plethora of sources. Damaged DNA, if not promptly recognized and repaired, can result in accumulation of mutations and can lead to genomic instability. Loss of genomic integrity is a predisposition for several genetic disorders as well as cancer. For a detailed introduction to DNA damage and repair read this post.
Defects in DNA repair
BRCA1 and BRCA2 genes encode proteins involved in DNA double-strand break repair by homologous recombination (HR). These genes are frequently mutated in several cancers including breast, ovarian and prostate cancers. BRCA1/2 play critical roles in suppressing R-loop formation by recruiting specific helicases, thereby preventing genomic instability. Cells deficient in BRCA1/2 are incapable of repairing DNA replication forks correctly and result in stalled forks, and overall display higher levels of single-strand DNA gaps. RecQ helicases such as WRN, BLM and FANCJ play key roles in unwinding DNA secondary structures such as G-quadruplexes; the accumulation of which results in genomic instability and increased cancer risk. Human fibroblasts deficient in WRN or BLM helicases are predicted to significantly up-regulate transcription of G-quadruplex forming sequences. Fanconi Anemia (FA) family of genes are mutated in cancers such as acute myeloid leukemia and squamous cell carcinoma. FA genes are crucial for repairing interstrand crosslinks; FA core complex is able to stably bind to DNA replication forks and facilitates recruitment of other FA proteins to ensure crosslink removal and repair by HR.
Targeting DNA repair defects in cancer therapy
Traditionally, radiation and chemotherapy have been used to treat cancers. In an effort to decrease cellular toxicity and increase selectivity, proteins in DNA damage repair pathways can be targeted for cancer therapy. PARP inhibitors (PARPi) offer selective killing of HR-deficient cancer cells. Several PAPRis are approved for use or are currently in clinical trials (Olaparib, Niraparib, Veliparib). PARPis impair base excision repair resulting in accumulation of single-strand breaks (ultimately double-strand breaks) in the genome. Cancer cells deficient in HR are incapable of repairing these breaks leading to their death. PARP1 is crucial for maturation of Okazaki fragments in DNA replication. As discussed previously, since BRCA1/2 deficient cancer cells are incapable of repairing single-strand breaks at replication forks, use of PARPis in cancers where BRCA1/2 is frequently mutated can prove to be a beneficial therapeutic strategy. Inhibitors of proteins ATR, CHK1, and WEE1 function in a similar manner and have been approved for use. Inhibiting proteins DNA-PK and ATM has been shown to sensitize cancer cells to chemo and radiation therapy. Loss of both proteins inhibits cell proliferation and is synthetically lethal. Combinatorial use of DNA-PKi and ATRi prevents reappearance of CHK1 phosphorylation and enhances efficacy of ATRi.
In summary, although defects in DNA repair mechanisms render cells vulnerable to DNA damage and cause several disease states including cancer, thorough understanding of DNA repair mechanisms and the functioning of proteins involved will help expand therapeutic strategies to combat cancer and overcome limitations to currently available therapeutics.
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