共查询到20条相似文献,搜索用时 46 毫秒
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Jawhari A Lainé JP Dubaele S Lamour V Poterszman A Coin F Moras D Egly JM 《The Journal of biological chemistry》2002,277(35):31761-31767
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Valentyn Oksenych Bruno Bernardes de Jesus Alexander Zhovmer Jean‐Marc Egly Frédéric Coin 《The EMBO journal》2009,28(19):2971-2980
XPB and XPD subunits of TFIIH are central genome caretakers involved in nucleotide excision repair (NER), although their respective role within this DNA repair pathway remains difficult to delineate. To obtain insight into the function of XPB and XPD, we studied cell lines expressing XPB or XPD ATPase‐deficient complexes. We show the involvement of XPB, but not XPD, in the accumulation of TFIIH to sites of DNA damage. Recruitment of TFIIH occurs independently of the helicase activity of XPB, but requires two recently identified motifs, a R‐E‐D residue loop and a Thumb‐like domain. Furthermore, we show that these motifs are specifically involved in the DNA‐induced stimulation of the ATPase activity of XPB. Together, our data demonstrate that the recruitment of TFIIH to sites of damage is an active process, under the control of the ATPase motifs of XPB and suggest that this subunit functions as an ATP‐driven hook to stabilize the binding of the TFIIH to damaged DNA. 相似文献
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Cellular DNA damage response is critical to preserving genomic integrity
following exposure to genotoxic stress. A complex series of networks and
signaling pathways become activated after DNA damage and trigger the appropriate
cellular response, including cell cycle arrest, DNA repair, and apoptosis. The
response elicited is dependent upon the type and extent of damage sustained,
with the ultimate goal of preventing propagation of the damaged DNA. A major
focus of our studies is to determine the cellular pathways involved in
processing damage induced by altered helical structures, specifically triplexes.
Our lab has demonstrated that the TFIIH factor XPD occupies a central role in
triggering apoptosis in response to triplex-induced DNA strand breaks. We have
shown that XPD co-localizes with γH2AX, and its presence is required for the
phosphorylation of H2AX tyrosine142, which stimulates the signaling pathway to
recruit pro-apoptotic factors to the damage site. Herein, we examine the
cellular pathways activated in response to triplex formation and discuss our
finding that suggests that XPD-dependent apoptosis plays a role in preserving
genomic integrity in the presence of excessive structurally induced DNA
damage. 相似文献
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DNA sequences capable of forming triplexes are prevalent in the human genome and have been found to be intrinsically mutagenic. Consequently, a balance between DNA repair and apoptosis is critical to counteract their effect on genomic integrity. Using triplex-forming oligonucleotides to synthetically create altered helical distortions, we have determined that pro-apoptotic pathways are activated by the formation of triplex structures. Moreover, the TFIIH factor, XPD, occupies a central role in triggering apoptosis in response to triplex-induced DNA strand breaks. Here, we show that triplexes are capable of inducing XPD-independent double strand breaks, which result in the formation of γH2AX foci. XPD was subsequently recruited to the triplex-induced double strand breaks and co-localized with γH2AX at the damage site. Furthermore, phosphorylation of H2AX tyrosine 142 was found to stimulate the signaling pathway of XPD-dependent apoptosis. We suggest that this mechanism may play an active role in minimizing genomic instability induced by naturally occurring noncanonical structures, perhaps protecting against cancer initiation. 相似文献