Serine ADP-ribosylation in DNA-damage response regulation

PARP1 activity is regulated by its cofactor HPF1. The binding of HPF1 on PARP1 controls the grafting of ADP-ribose moieties on serine residues of proteins nearby the DNA lesions, mainly PARP1 and histones. However, the impact of HPF1 on DNA repair regulated by PARP1 remains unclear. Here, we show that HPF1 controls both the number and the length of the ADP-ribose chains generated by PARP1 at DNA lesions. We demonstrate that HPF1-dependent histone ADP-ribosylation, rather than auto-modification of PARP1, triggers the rapid unfolding of the chromatin structure at the DNA damage sites and promotes the recruitment of the repair factors CHD4 and CHD7. Together with the observation that HPF1 contributes to efficient repair both by homologous recombination and non-homologous end joining, our findings highlight the key roles played by this PARP1 cofactor at early stages of the DNA damage response.

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Poly-ADP ribosylation in DNA damage response and cancer therapy

Mutation Research/Reviews in Mutation Research ◽

10.1016/j.mrrev.2017.09.004 ◽

2019 ◽

Vol 780 ◽

pp. 82-91 ◽

Cited By ~ 13

Author(s):

Wei-Hsien Hou ◽

Shih-Hsun Chen ◽

Xiaochun Yu

Keyword(s):

Dna Damage ◽

Cancer Therapy ◽

Dna Damage Response ◽

Adp Ribosylation ◽

Damage Response

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The Making and Breaking of Serine-ADP-Ribosylation in the DNA Damage Response

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.745922 ◽

2021 ◽

Vol 9 ◽

Author(s):

Kira Schützenhofer ◽

Johannes Gregor Matthias Rack ◽

Ivan Ahel

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Posttranslational Modification ◽

Chain Elongation ◽

Therapeutic Targeting ◽

Adp Ribosylation ◽

Damage Response ◽

Primary Amino ◽

Auxiliary Factor ◽

Amino Acid Acceptor

ADP-ribosylation is a widespread posttranslational modification that is of particular therapeutic relevance due to its involvement in DNA repair. In response to DNA damage, PARP1 and 2 are the main enzymes that catalyze ADP-ribosylation at damage sites. Recently, serine was identified as the primary amino acid acceptor of the ADP-ribosyl moiety following DNA damage and appears to act as seed for chain elongation in this context. Serine-ADP-ribosylation strictly depends on HPF1, an auxiliary factor of PARP1/2, which facilitates this modification by completing the PARP1/2 active site. The signal is terminated by initial poly(ADP-ribose) chain degradation, primarily carried out by PARG, while another enzyme, (ADP-ribosyl)hydrolase 3 (ARH3), specifically cleaves the terminal seryl-ADP-ribosyl bond, thus completing the chain degradation initiated by PARG. This review summarizes recent findings in the field of serine-ADP-ribosylation, its mechanisms, possible functions and potential for therapeutic targeting through HPF1 and ARH3 inhibition.

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