PARP1
小结
PARP1是抑癌基因，编码一种核蛋白修饰酶，参与DNA修复途径。编码蛋白将ADP-核糖基转移到靶蛋白。PARP1活性涉及多种生物学过程，包括DNA修复、DNA复制、转录和染色质重塑。诱导DNA损伤后，PARP1与单链断裂位点结合，并将DNA修复蛋白引入损伤部位。PARP1也是调节其他生理和致癌过程的关键因素，包括维持胚胎发育、细胞重编程和转录调控的多能性。功能研究证明，PARP1缺失会导致基因组不稳定和对DNA损伤诱导的细胞死亡的抗性。PARP1在多种人类癌症中高表达，然而，PARP1突变发生频率比较罕见。
PARP1 encodes a nuclear protein modifier enzyme involved in the DNA repair pathway. PARP1 inhibition has been shown to be effective in germline BRCA-deficient tumors, triple-negative breast cancer (TNBC), chronic lymphocytic leukemia, and ovarian serous papillary carcinoma. PARP1 encodes a nuclear localized poly(ADP-ribose) polymerase that transfers an ADP-ribose group to target proteins. PARP1 activity has been implicated in several biological processes including DNA repair, DNA replication, transcription, and chromatin remodeling. After induction of DNA damage, PARP1 binds to sites of single-strand breaks and recruits DNA repair proteins to the site of damage. PARP1 is also a key factor in regulating other biological and oncogenic processes, including maintenance of pluripotency in embryonic development, cell reprogramming and transcriptional regulation. Functional studies have demonstrated that PARP1 loss leads to genomic instability and resistance to DNA damage-induced cell death. PARP1 is highly expressed in several human cancers, however, PARP1 mutations are rare. In the absence of PARP1, single-strand breaks cause replication fork collapse resulting in double-stranded breaks and ultimately triggering DNA repair by homologous recombination pathways involving DNA repair genes such as BRCA1/2. PARP1 inhibitors have been developed to leverage the ability of PARP1 to induce double-strand breaks in cancers with mutations in DNA repair genes, such as BRCA1/2, resulting in inefficient repair and cell death. PARP inhibitors have also been shown to be efficacious in other tumor types that share clinicopathological characteristics with BRCA-mutant tumors (‘BRCAness’), such as triple-negative breast cancer (TNBC), chronic lymphocytic leukemia, and ovarian serous papillary carcinoma. The PARP1 inhibitor rucaparib has been approved for the treatment of BRCA-mutated ovarian cancer.