Mapping functional elements of the DNA damage response through base editor screens
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 eit...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724013986 |
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| author | Qian Pan Zhixuan Zhang Yangfang Xiong Ying Bao Tianxin Chen Ping Xu Zhiheng Liu Huazheng Ma Ying Yu Zhuo Zhou Wensheng Wei |
| author_facet | Qian Pan Zhixuan Zhang Yangfang Xiong Ying Bao Tianxin Chen Ping Xu Zhiheng Liu Huazheng Ma Ying Yu Zhuo Zhou Wensheng Wei |
| author_sort | Qian Pan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-39dec5f2658d4a64ba625de014d85260 |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-39dec5f2658d4a64ba625de014d852602025-08-20T01:54:53ZengElsevierCell Reports2211-12472024-12-01431211504710.1016/j.celrep.2024.115047Mapping functional elements of the DNA damage response through base editor screensQian Pan0Zhixuan Zhang1Yangfang Xiong2Ying Bao3Tianxin Chen4Ping Xu5Zhiheng Liu6Huazheng Ma7Ying Yu8Zhuo Zhou9Wensheng Wei10Biomedical 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, ChinaBiomedical 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, ChinaBiomedical 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, ChinaBiomedical 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, ChinaBiomedical 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, ChinaBiomedical 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, ChinaBiomedical 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, ChinaBiomedical 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, ChinaBiomedical 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, ChinaBiomedical 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, ChinaBiomedical 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124724013986CP: Molecular biology |
| spellingShingle | Qian Pan Zhixuan Zhang Yangfang Xiong Ying Bao Tianxin Chen Ping Xu Zhiheng Liu Huazheng Ma Ying Yu Zhuo Zhou Wensheng Wei Mapping functional elements of the DNA damage response through base editor screens Cell Reports CP: Molecular biology |
| title | Mapping functional elements of the DNA damage response through base editor screens |
| title_full | Mapping functional elements of the DNA damage response through base editor screens |
| title_fullStr | Mapping functional elements of the DNA damage response through base editor screens |
| title_full_unstemmed | Mapping functional elements of the DNA damage response through base editor screens |
| title_short | Mapping functional elements of the DNA damage response through base editor screens |
| title_sort | mapping functional elements of the dna damage response through base editor screens |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724013986 |
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