Mapping functional elements of the DNA damage response through base editor screens
Qian Pan,
Zhixuan Zhang,
Yangfang Xiong,
Ying Bao,
Tianxin Chen,
Ping Xu,
Zhiheng Liu,
Huazheng Ma,
Ying Yu,
Zhuo Zhou,
Wensheng Wei
Affiliations
Qian Pan
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking–Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
Zhixuan Zhang
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking–Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
Yangfang Xiong
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking–Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
Ying Bao
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking–Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Changping Laboratory, Beijing 102206, China
Tianxin Chen
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking–Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
Ping Xu
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking–Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
Zhiheng Liu
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking–Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
Huazheng Ma
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking–Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
Ying Yu
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking–Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China
Zhuo Zhou
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking–Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou 215123, Jiangsu, China
Wensheng Wei
Biomedical Pioneering Innovation Center, Beijing Advanced Innovation Center for Genomics, Peking–Tsinghua Center for Life Sciences, Peking University Genome Editing Research Center, State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing 100871, China; Changping Laboratory, Beijing 102206, China; Corresponding author
Summary: 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.
