Targeting the DNA damage response in cancer

MedComm, Год журнала: 2024, Номер 5(11)

Опубликована: Окт. 31, 2024

DNA damage response (DDR) pathway is the coordinated cellular network dealing with identification, signaling, and repair of damage. It tightly regulates cell cycle progression promotes to minimize daughter cells. Key proteins involved in DDR are frequently mutated/inactivated human cancers promote genomic instability, a recognized hallmark cancer. Besides being an intrinsic property tumors, also represents unique therapeutic opportunity. Indeed, inhibition expected delay repair, causing persistent unrepaired breaks, interfere progression, sensitize cancer cells several DNA-damaging agents, such as radiotherapy chemotherapy. In addition, defects have been shown render these more dependent on remaining pathways, which could be targeted very specifically (synthetic lethal approach). Research over past two decades has led synthesis testing hundreds small inhibitors against key proteins, some antitumor activity cancers. parallel, search for synthetic lethality interaction broadening use inhibitors. this review, we discuss state-of-art ataxia-telangiectasia mutated, ataxia-telangiectasia-and-Rad3-related protein, checkpoint kinase 1, Wee1 Polθ inhibitors, highlighting results obtained ongoing clinical trials both monotherapy combination chemotherapy radiotherapy.

Язык: Английский

Leading and lagging strand abasic sites differentially affect vertebrate replisome progression but involve analogous bypass mechanisms

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 9, 2025

Abasic sites are one of the most frequent forms DNA damage that interfere with replication. However, abasic exhibit complex effects because they can be processed into other types damage. Thus, it remains poorly understood how affect replisome progression, which replication-coupled repair pathways elicit, and whether this is affected by template strand damaged. Using Xenopus egg extracts, we developed an approach to analyze replication containing a site-specific, stable site on leading or lagging template. We show robustly stall synthesis nascent strands but exert different when encountered At AP site, replisomes ∼100 bp from lesion until bypassed converging fork triggers termination. progression unaffected reprimed downstream, generating post-replicative gap, then bypassed. Despite both rely translesion for bypass. Our results detail similarities differences between vertebrate

Язык: Английский