Checkpoint Kinase ATR Promotes Nucleotide Excision Repair of UV-induced DNA Damage via Physical Interaction with Xeroderma Pigmentosum Group A
Open accessAbstract
In response to DNA damage, eukaryotic cells activate a series of DNA damage-dependent pathways that serve to arrest cell cycle progression and remove DNA damage. Coordination of cell cycle arrest and damage repair is critical for maintenance of genomic stability. However, this process is still poorly understood. Nucleotide excision repair (NER) and the ATR-dependent cell cycle checkpoint are the major pathways responsible for repair of UV-induced DNA damage. Here we show that ATR physically interacts with the NER factor Xeroderma pigmentosum group A (XPA). Using a mass spectrometry-based protein footprinting method, we found that ATR interacts with a helix-turn-helix motif in the minimal DNA-binding domain of XPA where an ATR phosphorylation site (serine 196) is located. XPA-deficient cells complemented with XPA containing a point mutation of S196A displayed a reduced repair efficiency of cyclobutane pyrimidine dimers as compared with cells complemented with wild-type XPA, although no effect was observed for repair of (6-4) photoproducts. This suggests that the ATR-dependent phosphorylation of XPA may promote NER repair of persistent DNA damage. In addition, a K188A point mutation of XPA that disrupts the ATR-XPA interaction inhibits the nuclear import of XPA after UV irradiation and, thus, significantly reduced DNA repair efficiency. By contrast, the S196A mutation has no effect on XPA nuclear translocation. Taken together, our results suggest that the ATR-XPA interaction mediated by the helix-turn-helix motif of XPA plays an important role in DNA-damage responses to promote cell survival and genomic stability after UV irradiation.
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Normal UV-induced nuclear translocation of cytosolic XPA is lost with the Lys188Ala mutation, while the Ser196Ala mutation has no effect on XPA nuclear translocation.
“Moreover, the normal UV- induced nuclear translocation of cytosolic XPA was lost with the Lys188Ala mutation. However, the Ser196Ala mutation had no effect on XPA’s nuclear translocation.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [81]
A Lys188Ala mutation disrupts the ATR-XPA interaction and significantly reduces DNA repair efficiency.
“Shell’s structure-function studies also found that the Lys188 residue, which is nearby in the same helical DBD of XPA, was critical since a Lys188Ala mutation disrupted the ATR-XPA interaction, thus significantly reducing DNA repair efficiency 81.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [81]
ATR interacts with XPA upon UV irradiation.
“Furthermore, ATR was shown to interact with XPA upon UV irradiation [51]”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [51]
XPA nuclear foci formation after UV irradiation depends on ATR.
“at nuclear foci after UV irradiation is dependent upon ATR.”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [101]
Phosphorylation of XPA after UV irradiation is not needed for XPA foci formation.
“ATR also seems to be responsible for XPA phosphorylation after UV radiations, although this modification is not required for XPA foci formation [100–102].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [101]
ATR is responsible for phosphorylation of XPA after UV irradiation.
“ATR also seems to be responsible for XPA phosphorylation after UV radiations, although this modification is not required for XPA foci formation [100–102].”
From Mind the gap: keeping UV lesions in check (2011) · cites this paper as [101]
Prior work suggested that ATR influences NER in other cell types.
“Since prior work by others suggested that ATR influenced NER in other cell types (Shell et al., 2009; Wu et al., 2007; Wu et al., 2006)”
From RETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage (2014) · cites this paper as Shell et al., 2009
Prior studies in other systems show UV-dependent interactions between ATR and XPA.
“Although studies in other systems demonstrate UV-dependent ATR-XPA interactions (Dong et al., 2010; Shell et al., 2009; Wu et al., 2007)”
From RETRACTED: PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage (2014) · cites this paper as Shell et al., 2009
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References 44 · Cited by 86
- Authors
- Shell, S. M., Li, Z., Shkriabai, N., Kvaratskhelia, M., Brosey, C., Serrano, M. A., Chazin, W. J., Musich, P. R., & Zou, Y.
- Affiliations
- East Tennessee State University (US)
- The Ohio State University (US)
- Vanderbilt University (US)
- Corresponding author
- Zou, Yue
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2009-09
- Volume
- 284
- Issue
- 36
- Pages
- 24213-24222
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2782015
- OpenAlex
- W1967049460
- Cited by
- 86
- References
- 44
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 5 · 2021: 2 · 2020: 3 · 2019: 6 · 2018: 5 · 2017: 7 · 2016: 8 · 2015: 3 · 2014: 7 · 2013: 8 · 2012: 4
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons - East Tennessee State University (East Tennessee State University) (submittedVersion, cc-by)
- Funders
- National Institute on Aging (AG031503, R03AG031503)
- National Cancer Institute (R56CA086927, CA-092584, R01CA086927, CA-86927, P01CA092584)
- National Institute of General Medical Sciences (GM065484, T32GM008320, R01GM065484)
- National Institute of Allergy and Infectious Diseases (K02AI077341, AI077341)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- ATR kinase, XPA, nucleotide excision repair, UV-induced DNA damage, helix-turn-helix motif, cyclobutane pyrimidine dimers, 6-4 photoproducts, genome stability, DNA damage response
- MeSH terms
- Animals, Cell Line, Cell Nucleus, Cell Survival, DNA Damage, DNA Repair, Humans, Phosphorylation, Protein Binding, Mass Spectrometry, Ultraviolet Rays, Protein Serine-Threonine Kinases, Point Mutation, Cell Cycle Proteins, Amino Acid Motifs, Active Transport, Cell Nucleus, Xeroderma Pigmentosum Group A Protein, Ataxia Telangiectasia Mutated Proteins
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