Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C

Abstract

Disruption of the nucleotide excision repair (NER) pathway by mutations can cause xeroderma pigmentosum, a syndrome predisposing affected individuals to development of skin cancer. The xeroderma pigmentosum C (XPC) protein is essential for initiating global genome NER by recognizing the DNA lesion and recruiting downstream factors. Here we show that inhibition of the deacetylase and longevity factor SIRT1 impairs global genome NER through suppressing the transcription of XPC in a SIRT1 deacetylase-dependent manner. SIRT1 enhances XPC expression by reducing AKTdependent nuclear localization of the transcription repressor of XPC. Finally, we show that SIRT1 levels are significantly reduced in human skin tumors from Caucasian patients, a population at highest risk. These findings suggest that SIRT1 acts as a tumor suppressor through its role in DNA repair.ucleotide excision repair (NER) is a versatile DNA repair pathway that eliminates a wide variety of helix-distorting base lesions, including UV radiation-induced cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts (6-4PPs) (1, 2), as well as bulky adducts induced by numerous chemical compounds. Defects in NER by mutations cause the autosomal recessive xeroderma pigmentosum (XP) and Cockayne syndromes (3-5). XP patients are clinically characterized by cutaneous sensitivity to sunlight exposure and a predisposition to skin cancer. Seven NER-deficient genetic complementation groups of XP (XP-A to -G) have been identified, and all of the corresponding genes have now been cloned (3-5).Mammalian NER consists of two distinct subpathways: global genome NER (GG-NER), which operates throughout the genome, and transcription-coupled NER (TC-NER), which specifically removes lesions on the transcribed DNA strand of active genes. A major difference between these two pathways appears to lie in the strategies for detecting damaged bases. Accumulating evidence indicates that the XP group C (XPC) protein plays an essential role in GG-NER-specific damage recognition (6-8). Although biochemical and genetic analyses have characterized the function of XPC in considerable detail, much remains to be elucidated with regard to its regulation and interaction with other critical cellular pathways.Sirtuin 1 (SIRT1), a mammalian counterpart of the yeast silent information regulator 2 (Sir2) and a proto member of the sirtuin family, is an NAD-dependent longevity-promoting deacetylase. SIRT1 is crucial for cell survival, metabolism, senescence, and stress response in several cell types and tissues (9-13). Both histone and nonhistone targets of SIRT1 have been identified, including FOXO, p53, and PPARγ (10,12,14). SIRT1 has been implicated as an important player in cancer. However, it remains unclear whether SIRT1 serves as a tumor suppressor or a tumor promoter (13-16). SIRT1 expression is relatively higher in many malignancies, including colon, breast, prostate, and skin cancers and leukemia, as compared with their corresponding normal tissues (17)(18)(19)(20)(21)(22). But the specific c...

SIRT1 promotes tumorigenesis of hepatocellular carcinoma through PI3K/PTEN/AKT signaling

“…Acetylation of PTEN has been shown to inhibit its activity and thus activate AKT (35,36). We used immunoblotting analysis in the same cellular models as shown in Fig.…”

Quantitative Acetylome Analysis Reveals the Roles of SIRT1 in Regulating Diverse Substrates and Cellular Pathways

“…DNA repair is a crucial cellular pathway that autonomously maintains genome integrity and previously known to be regulated by SIRT1 (37,38). Among various types of repair mechanisms, our study showed that SIRT1 may play a profound role in regulating base excision repair (BER) and mismatch repair (MR), two types of single-strand DNA repair mechanisms.…”

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…SIRT1 deacetylates two lysines of the core NER protein XPA (xeroderma pigmentosum group A); this reaction is necessary for the full efficiency of UV damage removal [50]. SIRT1 also relieves the repression of the XPC gene coding for a protein that recognizes DNA lesion and recruits other NER components [135]. Table II.…”