Coordinated regulation of XPA stability by ATR and HERC2 during nucleotide excision repair
Abstract
ATR (ATM and Rad3-related) is an essential regulator of the nucleotide excision repair (NER) mechanism. For NER activation, ATR phosphorylates XPA, the rate-limiting factor in the NER pathway. However, the role of XPA phosphorylation at serine 196 by ATR has been elusive. Here we show that ATR-mediated XPA phosphorylation enhances XPA stability by inhibiting HERC2-mediated ubiquitination and subsequent degradation. We analyzed stabilization of XPA with substitutions of Ser 196 either to aspartate (S196D), a phosphomimetic mutation, or to alanine (S196A), a phosphodeficient mutation. Upon ultraviolet damage, ATR facilitated HERC2 dissociation from the XPA complex to induce XPA stabilization. However, this regulation was abrogated in S196A-complemented XPA-deficient cells due to persistent association of HERC2 with this XPA complex, resulting in enhanced ubiquitination of S196A. Conversely, the S196D substitution showed delayed degradation kinetics compared with the wild-type and less binding with HERC2, resulting in reduced ubiquitination of S196D. We also found that XPA phosphorylation enhanced the chromatin retention of XPA, the interaction with its binding partners following DNA damage. Taken together, our study presents a novel control mechanism in the NER pathway by regulating the steady-state level of XPA through posttranslational modifications by which ATR-mediated phosphorylation induces XPA stabilization by antagonizing HERC2-catalyzed XPA ubiquitination.
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Phosphorylation of Ser196 in XPA by ATR appears to stabilize XPA against HERC2-mediated ubiquitinylation and degradation.
“The phosphorylation of Ser196 in XPA by ATR appears to stabilize XPA against HERC2-mediated ubiquitinylation and degradation 80.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [80]
The activity of NER and sensitization of cancer cells to chemotherapy can be regulated by transcriptional and post-transcriptional control of the XPA protein.
“Because of XPA’s crucial functions in NER, the activity of NER and sensitization of cancer cells to chemotherapy can be regulated by transcriptional and post-transcriptional control of the XPA protein [19], [20], [21], [22], [23], [24], [25], [26].”
From UV-Induced Nuclear Import of XPA Is Mediated by Importin-α4 in An ATR-Dependent Manner (2013) · cites this paper as [19]
The activity of NER and sensitization of cancer cells to chemotherapy can be regulated by transcriptional and post-transcriptional control of the XPA protein.
“Because of XPA’s crucial functions in NER, the activity of NER and sensitization of cancer cells to chemotherapy can be regulated by transcriptional and post-transcriptional control of the XPA protein [19], [20], [21], [22], [23], [24], [25], [26].”
From UV-Induced Nuclear Import of XPA Is Mediated by Importin-α4 in An ATR-Dependent Manner (2013) · cites this paper as [20]
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XPA is susceptible to proteolytic cleavage by cathepsin L during lysis of quiescent cells
Khan, S., Cvammen, W., Anabtawi, N., Choi, J., & Kemp, M. G. (2021) · DNA repair · doi:10.1016/j.dnarep.2021.103260 · Cited by 4 · see citing works
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Self-citationThe role of HECT-type E3 ubiquitin ligases in DNA damage response and repair
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DNA Damage: Cellular Responses, Repair, and Cancer Treatment
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RNAi and Chemical-Based High Content Screening for the Normalization of XPC Phenotyope
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PARylation at the Genome–Proteome Interface: Regulation of DNA Repair Protein Dynamics
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XPA lactylation is required for UV-induced DNA damage repair
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- Authors
- Lee, T.-H., Park, J.-M., Leem, S.-H., & Kang, T.-H.
- Affiliations
- Dong-A University (KR)
- Corresponding author
- Kang, T-H
- Venue
- Oncogene
- Published
- 2012-11-26
- Volume
- 33
- Issue
- 1
- Pages
- 19-25
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2057834096
- Semantic Scholar
- 1bf3be8064d195b05196a78ede616b8c503db07f
- Cited by
- 61
- References
- 49
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 4 · 2022: 3 · 2021: 8 · 2020: 6 · 2019: 7 · 2018: 3 · 2017: 5 · 2016: 6 · 2015: 4 · 2014: 6 · 2013: 3
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- XPA, ATR, HERC2, nucleotide excision repair, protein stability, ubiquitination, protein degradation, post-translational modification, UV damage, DNA damage response
- MeSH terms
- DNA Repair, Humans, Phosphorylation, RNA, Messenger, Gene Expression, Guanine Nucleotide Exchange Factors, Ubiquitin-Protein Ligases, Cell Line, Tumor, Xeroderma Pigmentosum Group A Protein, Ubiquitination, Protein Stability, Ataxia Telangiectasia Mutated Proteins
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