TY - JOUR
T1 - Werner protein cooperates with the XRCC4-DNA ligase IV complex in end-processing
AU - Kusumoto, Rika
AU - Dawut, Lala
AU - Marchetti, Caterina
AU - Jae, Wan Lee
AU - Vindigni, Alessandro
AU - Ramsden, Dale
AU - Bohr, Vilhelm A.
PY - 2008/7/15
Y1 - 2008/7/15
N2 - Werner syndrome is a rare human disease characterized by the premature onset of aging-associated pathologies, cancer predisposition, and genomic instability. The Werner protein (WRN), which is defective in Werner syndrome (WS) patients, belongs to the RecQ family helicases and interacts with several DNA metabolic proteins, including DNA repair factors and telomere associated proteins. Nonhomologous end-joining (NHEJ) is an important pathway in the repair of DNA double strand breaks (DSBs), and the DNA-PK complex, composed of the heterodimer Ku 70/86 and the DNA-PK catalytic subunit (DNA-PKcs), together with the XRCC4-DNA ligase IV complex (X4L4), are major factors. One of the most prominent protein interactions of WRN is with Ku 70/86, and it is possible that WRN is involved in NHEJ via its associations with Ku 70/86 and DNA-PKcs. This study demonstrates that WRN physically interacts with the major NHEJ factor, X4L4, which stimulates WRN exonuclease but not its helicase activity. The human RecQ helicase, BLM, which possesses only helicase activity, does not bind to X4L4, and its helicase activity is not affected by X4L4. In a DNA end-joining assay, we find that a substrate, which is processed by WRN, is ligated by X4L4, thus further supporting the significance of their functional interaction.
AB - Werner syndrome is a rare human disease characterized by the premature onset of aging-associated pathologies, cancer predisposition, and genomic instability. The Werner protein (WRN), which is defective in Werner syndrome (WS) patients, belongs to the RecQ family helicases and interacts with several DNA metabolic proteins, including DNA repair factors and telomere associated proteins. Nonhomologous end-joining (NHEJ) is an important pathway in the repair of DNA double strand breaks (DSBs), and the DNA-PK complex, composed of the heterodimer Ku 70/86 and the DNA-PK catalytic subunit (DNA-PKcs), together with the XRCC4-DNA ligase IV complex (X4L4), are major factors. One of the most prominent protein interactions of WRN is with Ku 70/86, and it is possible that WRN is involved in NHEJ via its associations with Ku 70/86 and DNA-PKcs. This study demonstrates that WRN physically interacts with the major NHEJ factor, X4L4, which stimulates WRN exonuclease but not its helicase activity. The human RecQ helicase, BLM, which possesses only helicase activity, does not bind to X4L4, and its helicase activity is not affected by X4L4. In a DNA end-joining assay, we find that a substrate, which is processed by WRN, is ligated by X4L4, thus further supporting the significance of their functional interaction.
UR - http://www.scopus.com/inward/record.url?scp=47249106520&partnerID=8YFLogxK
U2 - 10.1021/bi702325t
DO - 10.1021/bi702325t
M3 - Article
C2 - 18558713
AN - SCOPUS:47249106520
SN - 0006-2960
VL - 47
SP - 7548
EP - 7556
JO - Biochemistry
JF - Biochemistry
IS - 28
ER -