Sirtuin 1-mediated deacetylation of XPA DNA repair protein enhances its interaction with ATR protein and promotes cAMP-induced DNA repair of UV damage

Abstract

Edited by John M. Denu Blunted melanocortin 1 receptor (MC1R) signaling promotes melanocyte genomic instability in part by attenuating cAMPmediated DNA repair responses, particularly nucleotide excision repair (NER), which recognizes and clears mutagenic photodamage. cAMP-enhanced NER is mediated by interactions between the ataxia telangiectasia-mutated and Rad3-related (ATR) and xeroderma pigmentosum complementation group A (XPA) proteins. We now report a critical role for sirtuin 1 (SIRT1) in regulating ATR-mediated phosphorylation of XPA. SIRT1 deacetylates XPA at residues Lys-63, Lys-67, and Lys-215 to promote interactions with ATR. Mutant XPA containing acetylation mimetics at residues Lys-63, Lys-67, and Lys-215 exhibit blunted UV-dependent ATR-XPA interactions even in the presence of cAMP signals. ATR-mediated phosphorylation of XPA on Ser-196 enhances cAMP-mediated optimization of NER and is promoted by SIRT1-mediated deacetylation of XPA on Lys-63, Lys-67, and Lys-215. Interference with ATR-mediated XPA phosphorylation at Ser-196 by persistent acetylation of XPA at Lys-63, Lys-67, and Lys-215 delays repair of UV-induced DNA damage and attenuates cAMP-enhanced NER. Our study identifies a regulatory ATR-SIRT1-XPA axis in cAMPmediated regulation melanocyte genomic stability, involving SIRT1-mediated deacetylation (Lys-63, Lys-67, and Lys-215) and ATR-dependent phosphorylation (Ser-196) post-translational modifications of the core NER factor XPA.

NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential

“…[164][165][166][167] Similarly, DNA damage induces the relocalization of NAD + -dependent deacetylase SIRT1 to DNA breaks, which promotes DNA repair via opening the chromatin and recruiting the main DNA repair factors including KU70, NBS1, WRN, KAP1, XPA and APEX1. [168][169][170][171][172][173][174][175][176][177] Additionally, PARPs and sirtuins also simulate genomic damage-signaling kinases, including ATM, p53, DNA-PK, CIRBP and FOXOs, to accelerate DNA repair. [178][179][180][181][182] Given that DNA damage-activated PARPs account for up to 90% of cellular NAD + consumption, the DNA repair activity is highly dependent on the cellular NAD + concentration.…”

The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

“…HDACi combined with genotoxic agents results in UNG2 degradation, resulting in a robust cell death effect (Bao et al, 2020). SIRT1 interacts with xeroderma pigmentosum group A (XPA) in NER by directly deacetylating XPA or mediating XPA binding to ATR to prevent UV irradiation (Fan and Luo, 2010;Jarrett et al, 2018). HDAC10 is mainly involved in DNA mismatch repair by deacetylating mutS homolog 2 (MSH2) at K73 (Radhakrishnan et al, 2015).…”

Acetylation and Deacetylation of DNA Repair Proteins in Cancers

“…Furthermore, deacetylation on XPA (Lys63/67) by SIRT1 influenced the binding between XPA and RPA32, whereas Lys215 that is located in the ATRbinding region of XPA was deacetylated to enhance TC-NER activity by promoting the bond between ataxia-telangiectasia and Rad3 related (ATR) and XPA (63). By contrast, acetylation of XPA at Lys215 mediated by CBP might play a negative role in regulating XPA-protein interaction, which attenuated TC-NER capacity (64). XPG protein equipped with 3 ′ endonuclease activity is another core TC-NER factor that is necessary for DNA incision and lesion removal.…”