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Functional capacity of XRCC1 protein variants identified in DNA repair-deficient Chinese hamster ovary cell lines and the human population
- Source :
- Nucleic Acids Research, Nucleic acids research, vol 38, iss 15
- Publication Year :
- 2010
- Publisher :
- Oxford University Press, 2010.
-
Abstract
- XRCC1 operates as a scaffold protein in base excision repair, a pathway that copes with base and sugar damage in DNA. Studies using recombinant XRCC1 proteins revealed that: a C389Y substitution, responsible for the repair defects of the EM-C11 CHO cell line, caused protein instability; a V86R mutation abolished the interaction with POLbeta, but did not disrupt the interactions with PARP-1, LIG3alpha and PCNA; and an E98K substitution, identified in EM-C12, reduced protein integrity, marginally destabilized the POLbeta interaction, and slightly enhanced DNA binding. Two rare (P161L and Y576S) and two frequent (R194W and R399Q) amino acid population variants had little or no effect on XRCC1 protein stability or the interactions with POLbeta, PARP-1, LIG3alpha, PCNA or DNA. One common population variant (R280H) had no pronounced effect on the interactions with POLbeta, PARP-1, LIG3alpha and PCNA, but did reduce DNA-binding ability. When expressed in HeLa cells, the XRCC1 variants-excluding E98K, which was largely nucleolar, and C389Y, which exhibited reduced expression-exhibited normal nuclear distribution. Most of the protein variants, including the V86R POLbeta-interaction mutant, displayed normal relocalization kinetics to/from sites of laser-induced DNA damage: except for E98K and C389Y, and the polymorphic variant R280H, which exhibited a slightly shorter retention time at DNA breaks.
- Subjects :
- DNA Repair
DNA damage
DNA repair
CHO Cells
Genome Integrity, Repair and Replication
medicine.disease_cause
03 medical and health sciences
XRCC1
chemistry.chemical_compound
0302 clinical medicine
Cricetulus
Information and Computing Sciences
Cricetinae
medicine
Genetics
2.1 Biological and endogenous factors
Animals
Humans
Aetiology
030304 developmental biology
0303 health sciences
Mutation
biology
Chinese hamster ovary cell
Base excision repair
DNA
Biological Sciences
Molecular biology
Proliferating cell nuclear antigen
DNA-Binding Proteins
X-ray Repair Cross Complementing Protein 1
chemistry
Amino Acid Substitution
030220 oncology & carcinogenesis
biology.protein
Generic health relevance
Environmental Sciences
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 13624962 and 03051048
- Volume :
- 38
- Issue :
- 15
- Database :
- OpenAIRE
- Journal :
- Nucleic Acids Research
- Accession number :
- edsair.doi.dedup.....01ff45a40cefbf159d35a6ba6f5e57d5