Cargando…
PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage
Poly(ADP-ribose) polymerase-2 (PARP-2) is one of three human PARP enzymes that are potently activated during the cellular DNA damage response (DDR). DDR-PARPs detect DNA strand breaks, leading to a dramatic increase in their catalytic production of the posttranslational modification poly(ADP-ribose)...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2016
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770219/ https://www.ncbi.nlm.nih.gov/pubmed/26704974 http://dx.doi.org/10.1093/nar/gkv1376 |
_version_ | 1782418221821853696 |
---|---|
author | Riccio, Amanda A. Cingolani, Gino Pascal, John M. |
author_facet | Riccio, Amanda A. Cingolani, Gino Pascal, John M. |
author_sort | Riccio, Amanda A. |
collection | PubMed |
description | Poly(ADP-ribose) polymerase-2 (PARP-2) is one of three human PARP enzymes that are potently activated during the cellular DNA damage response (DDR). DDR-PARPs detect DNA strand breaks, leading to a dramatic increase in their catalytic production of the posttranslational modification poly(ADP-ribose) (PAR) to facilitate repair. There are limited biochemical and structural insights into the functional domains of PARP-2, which has restricted our understanding of how PARP-2 is specialized toward specific repair pathways. PARP-2 has a modular architecture composed of a C-terminal catalytic domain (CAT), a central Trp-Gly-Arg (WGR) domain and an N-terminal region (NTR). Although the NTR is generally considered the key DNA-binding domain of PARP-2, we report here that all three domains of PARP-2 collectively contribute to interaction with DNA damage. Biophysical, structural and biochemical analyses indicate that the NTR is natively disordered, and is only required for activation on specific types of DNA damage. Interestingly, the NTR is not essential for PARP-2 localization to sites of DNA damage. Rather, the WGR and CAT domains function together to recruit PARP-2 to sites of DNA breaks. Our study differentiates the functions of PARP-2 domains from those of PARP-1, the other major DDR-PARP, and highlights the specialization of the multi-domain architectures of DDR-PARPs. |
format | Online Article Text |
id | pubmed-4770219 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-47702192016-02-29 PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage Riccio, Amanda A. Cingolani, Gino Pascal, John M. Nucleic Acids Res Genome Integrity, Repair and Replication Poly(ADP-ribose) polymerase-2 (PARP-2) is one of three human PARP enzymes that are potently activated during the cellular DNA damage response (DDR). DDR-PARPs detect DNA strand breaks, leading to a dramatic increase in their catalytic production of the posttranslational modification poly(ADP-ribose) (PAR) to facilitate repair. There are limited biochemical and structural insights into the functional domains of PARP-2, which has restricted our understanding of how PARP-2 is specialized toward specific repair pathways. PARP-2 has a modular architecture composed of a C-terminal catalytic domain (CAT), a central Trp-Gly-Arg (WGR) domain and an N-terminal region (NTR). Although the NTR is generally considered the key DNA-binding domain of PARP-2, we report here that all three domains of PARP-2 collectively contribute to interaction with DNA damage. Biophysical, structural and biochemical analyses indicate that the NTR is natively disordered, and is only required for activation on specific types of DNA damage. Interestingly, the NTR is not essential for PARP-2 localization to sites of DNA damage. Rather, the WGR and CAT domains function together to recruit PARP-2 to sites of DNA breaks. Our study differentiates the functions of PARP-2 domains from those of PARP-1, the other major DDR-PARP, and highlights the specialization of the multi-domain architectures of DDR-PARPs. Oxford University Press 2016-02-29 2015-12-23 /pmc/articles/PMC4770219/ /pubmed/26704974 http://dx.doi.org/10.1093/nar/gkv1376 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Genome Integrity, Repair and Replication Riccio, Amanda A. Cingolani, Gino Pascal, John M. PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage |
title | PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage |
title_full | PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage |
title_fullStr | PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage |
title_full_unstemmed | PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage |
title_short | PARP-2 domain requirements for DNA damage-dependent activation and localization to sites of DNA damage |
title_sort | parp-2 domain requirements for dna damage-dependent activation and localization to sites of dna damage |
topic | Genome Integrity, Repair and Replication |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770219/ https://www.ncbi.nlm.nih.gov/pubmed/26704974 http://dx.doi.org/10.1093/nar/gkv1376 |
work_keys_str_mv | AT riccioamandaa parp2domainrequirementsfordnadamagedependentactivationandlocalizationtositesofdnadamage AT cingolanigino parp2domainrequirementsfordnadamagedependentactivationandlocalizationtositesofdnadamage AT pascaljohnm parp2domainrequirementsfordnadamagedependentactivationandlocalizationtositesofdnadamage |