Mapping functional elements of the DNA damage response through base editor screens

作者：Qian Pan, Zhixuan Zhang, Yangfang Xiong, Ying Bao, Tianxin Chen, Ping Xu, Zhiheng Liu, Huazheng Ma, Ying Yu, Zhuo Zhou, Wensheng Wei · 发表于：Cell Reports · 年份：2024 · DOI：10.1016/j.celrep.2024.115047 · 被引用次数：9 · 研究领域：CRISPR and Genetic Engineering、DNA Repair Mechanisms、PARP inhibition in cancer therapy

Maintaining genomic stability is vital for cellular equilibrium. In this study, we combined CRISPR-mediated base editing with pooled screening technologies to identify numerous mutations in lysine residues and protein-coding genes. The loss of these lysine residues and genes resulted in either sensitivity or resistance to DNA-damaging agents. Among the identified variants, we characterized both loss-of-function and gain-of-function mutations in response to DNA damage. Notably, we discovered that the K494 mutation of C17orf53 disrupts its interaction with RPA proteins, leading to increased sensitivity to cisplatin. Additionally, our analysis identified STK35 as a previously unrecognized gene involved in DNA damage response (DDR) pathways, suggesting that it may play a critical role in DNA repair. We believe that this resource will offer valuable insights into the broader functions of DNA damage response genes and accelerate research on variants relevant to cancer therapy.