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

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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Faculty Opinions recommendation of The FHA and BRCT domains recognize ADP-ribosylation during DNA damage response.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718078169.793491856 ◽

2014 ◽

Author(s):

Scott Kaufmann

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Adp Ribosylation ◽

Damage Response

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HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications

Nature Communications ◽

10.1038/s41467-021-27043-8 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Marie-France Langelier ◽

Ramya Billur ◽

Aleksandr Sverzhinsky ◽

Ben E. Black ◽

John M. Pascal

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Chain Elongation ◽

Dna Breaks ◽

Data Support ◽

Damage Response ◽

Hit And Run ◽

Dna Break ◽

Structural Insights ◽

In Cells

AbstractPARP1 and PARP2 produce poly(ADP-ribose) in response to DNA breaks. HPF1 regulates PARP1/2 catalytic output, most notably permitting serine modification with ADP-ribose. However, PARP1 is substantially more abundant in cells than HPF1, challenging whether HPF1 can pervasively modulate PARP1. Here, we show biochemically that HPF1 efficiently regulates PARP1/2 catalytic output at sub-stoichiometric ratios matching their relative cellular abundances. HPF1 rapidly associates/dissociates from multiple PARP1 molecules, initiating serine modification before modification initiates on glutamate/aspartate, and accelerating initiation to be more comparable to elongation reactions forming poly(ADP-ribose). This “hit and run” mechanism ensures HPF1 contributions to PARP1/2 during initiation do not persist and interfere with PAR chain elongation. We provide structural insights into HPF1/PARP1 assembled on a DNA break, and assess HPF1 impact on PARP1 retention on DNA. Our data support the prevalence of serine-ADP-ribose modification in cells and the efficiency of serine-ADP-ribose modification required for an acute DNA damage response.

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Faculty Opinions recommendation of Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718013253.793477675 ◽

2013 ◽

Author(s):

Junjie Chen

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Adp Ribosylation ◽

Damage Response

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The role of poly ADP-ribosylation in the first wave of DNA damage response

Nucleic Acids Research ◽

10.1093/nar/gkx565 ◽

2017 ◽

Vol 45 (14) ◽

pp. 8129-8141 ◽

Cited By ~ 59

Author(s):

Chao Liu ◽

Aditi Vyas ◽

Muzaffer A. Kassab ◽

Anup K. Singh ◽

Xiaochun Yu

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Adp Ribosylation ◽

Damage Response

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Mechanistic insights into the three steps of poly(ADP-ribosylation) reversal

Nature Communications ◽

10.1038/s41467-021-24723-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Johannes Gregor Matthias Rack ◽

Qiang Liu ◽

Valentina Zorzini ◽

Jim Voorneveld ◽

Antonio Ariza ◽

...

Keyword(s):

Dna Damage ◽

Structural Analysis ◽

Dna Damage Response ◽

Posttranslational Modification ◽

Molecular Basis ◽

Branched Polymers ◽

Coordination Geometry ◽

Cellular Processes ◽

Damage Response ◽

Hydrolysis Of

AbstractPoly(ADP-ribosyl)ation (PAR) is a versatile and complex posttranslational modification composed of repeating units of ADP-ribose arranged into linear or branched polymers. This scaffold is linked to the regulation of many of cellular processes including the DNA damage response, alteration of chromatin structure and Wnt signalling. Despite decades of research, the principles and mechanisms underlying all steps of PAR removal remain actively studied. In this work, we synthesise well-defined PAR branch point molecules and demonstrate that PARG, but not ARH3, can resolve this distinct PAR architecture. Structural analysis of ARH3 in complex with dimeric ADP-ribose as well as an ADP-ribosylated peptide reveal the molecular basis for the hydrolysis of linear and terminal ADP-ribose linkages. We find that ARH3-dependent hydrolysis requires both rearrangement of a catalytic glutamate and induction of an unusual, square-pyramidal magnesium coordination geometry.

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