Dissection of the molecular defects caused by pathogenic mutations in the DNA repair factor XPC.

Abstract:

:XPC is responsible for DNA damage sensing in nucleotide excision repair (NER). Mutations in XPC lead to a defect in NER and to xeroderma pigmentosum (XP-C). Here, we analyzed the biochemical properties behind mutations found within three patients: one amino acid substitution (P334H, XP1MI, and GM02096), one amino acid incorporation in a conserved domain (697insVal, XP8BE, and GM02249), and a stop mutation (R579St, XP67TMA, and GM14867). Using these mutants, we demonstrated that HR23B stabilizes XPC on DNA and protects it from degradation. XPC recruits the transcription/repair factor TFIIH and stimulates its XPB ATPase activity to initiate damaged DNA opening. In an effort to understand the severity of XP-C phenotypes, we also demonstrated that single mutations in XPC perturb other repair processes, such as base excision repair (e.g., the P334H mutation prevents the stimulation of Ogg1 glycosylase because it thwarts the interaction between XPC and Ogg1), thereby leading to a deeper understanding of the molecular repair defect of the XP-C patients.

journal_name

Mol Cell Biol

authors

Bernardes de Jesus BM,Bjørås M,Coin F,Egly JM

doi

10.1128/MCB.00781-08

subject

Has Abstract

pub_date

2008-12-01 00:00:00

pages

7225-35

issue

23

eissn

0270-7306

issn

1098-5549

pii

MCB.00781-08

journal_volume

28

pub_type

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