PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ

Adam Harvey, Nicholas Mielke, Julia W. Grimstead, Rhiannon E. Jones, Thanh Nguyen, Matthew Mueller, Duncan M. Baird, Eric A Hendrickson

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Poly-ADP ribose polymerase 1 (PARP1) is clinically important because of itssynthetic lethality with breast cancer allele 1 and 2 mutations, which are causativefor inherited breast and ovarian cancers. Biochemically, PARP1 is a single-strandedDNA break repair protein that is needed for preserving genomic integrity. In addition,PARP1 has been implicated in a veritable plethora of additional cellular pathwaysand thus its precise contribution(s) to human biology has remained obscure. To helpaddress this deficiency, we utilized gene editing to construct genetically-null PARP1human cancer cells. We found a minor role for PARP1 in an alternative form of DNAdouble-strand break (DSB) repair, but only when these cells were deficient for theclassical form of DSB repair. Despite being proficient for DSB repair, however, cellcycle progression defects and elevated endogenous DNA damage signaling wereobserved. These deficiencies were instead linked to telomere defects, where PARP1-/-cells had short telomeres that co-localized with markers of endogenous DNA damageand were compromised in their ability to escape a telomere-driven crisis. Our datasuggest that while PARP1 does not participate significantly in DNA DSB repair itself,it does prevent the incidence of telomeric DSBs, which, in turn, can drive genomicinstability.

Original languageEnglish (US)
Pages (from-to)34821-34837
Number of pages17
JournalOncotarget
Volume9
Issue number78
DOIs
StatePublished - Oct 1 2018

Fingerprint

Telomere
Breast Neoplasms
Genetic Markers
Ovarian Neoplasms
DNA Damage
Poly (ADP-Ribose) Polymerase-1
Alleles
Mutation
DNA
Incidence
Neoplasms
Proteins

Keywords

  • Gene editing
  • HDR
  • NHEJ
  • PARP1
  • Telomeres

Cite this

Harvey, A., Mielke, N., Grimstead, J. W., Jones, R. E., Nguyen, T., Mueller, M., ... Hendrickson, E. A. (2018). PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ. Oncotarget, 9(78), 34821-34837. https://doi.org/10.18632/oncotarget.26201

PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ. / Harvey, Adam; Mielke, Nicholas; Grimstead, Julia W.; Jones, Rhiannon E.; Nguyen, Thanh; Mueller, Matthew; Baird, Duncan M.; Hendrickson, Eric A.

In: Oncotarget, Vol. 9, No. 78, 01.10.2018, p. 34821-34837.

Research output: Contribution to journalArticle

Harvey, A, Mielke, N, Grimstead, JW, Jones, RE, Nguyen, T, Mueller, M, Baird, DM & Hendrickson, EA 2018, 'PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ', Oncotarget, vol. 9, no. 78, pp. 34821-34837. https://doi.org/10.18632/oncotarget.26201
Harvey A, Mielke N, Grimstead JW, Jones RE, Nguyen T, Mueller M et al. PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ. Oncotarget. 2018 Oct 1;9(78):34821-34837. https://doi.org/10.18632/oncotarget.26201
Harvey, Adam ; Mielke, Nicholas ; Grimstead, Julia W. ; Jones, Rhiannon E. ; Nguyen, Thanh ; Mueller, Matthew ; Baird, Duncan M. ; Hendrickson, Eric A. / PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ. In: Oncotarget. 2018 ; Vol. 9, No. 78. pp. 34821-34837.
@article{9245c08409884b648f2780bd1b4e0e44,
title = "PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ",
abstract = "Poly-ADP ribose polymerase 1 (PARP1) is clinically important because of itssynthetic lethality with breast cancer allele 1 and 2 mutations, which are causativefor inherited breast and ovarian cancers. Biochemically, PARP1 is a single-strandedDNA break repair protein that is needed for preserving genomic integrity. In addition,PARP1 has been implicated in a veritable plethora of additional cellular pathwaysand thus its precise contribution(s) to human biology has remained obscure. To helpaddress this deficiency, we utilized gene editing to construct genetically-null PARP1human cancer cells. We found a minor role for PARP1 in an alternative form of DNAdouble-strand break (DSB) repair, but only when these cells were deficient for theclassical form of DSB repair. Despite being proficient for DSB repair, however, cellcycle progression defects and elevated endogenous DNA damage signaling wereobserved. These deficiencies were instead linked to telomere defects, where PARP1-/-cells had short telomeres that co-localized with markers of endogenous DNA damageand were compromised in their ability to escape a telomere-driven crisis. Our datasuggest that while PARP1 does not participate significantly in DNA DSB repair itself,it does prevent the incidence of telomeric DSBs, which, in turn, can drive genomicinstability.",
keywords = "Gene editing, HDR, NHEJ, PARP1, Telomeres",
author = "Adam Harvey and Nicholas Mielke and Grimstead, {Julia W.} and Jones, {Rhiannon E.} and Thanh Nguyen and Matthew Mueller and Baird, {Duncan M.} and Hendrickson, {Eric A}",
year = "2018",
month = "10",
day = "1",
doi = "10.18632/oncotarget.26201",
language = "English (US)",
volume = "9",
pages = "34821--34837",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "78",

}

TY - JOUR

T1 - PARP1 is required for preserving telomeric integrity but is dispensable for A-NHEJ

AU - Harvey, Adam

AU - Mielke, Nicholas

AU - Grimstead, Julia W.

AU - Jones, Rhiannon E.

AU - Nguyen, Thanh

AU - Mueller, Matthew

AU - Baird, Duncan M.

AU - Hendrickson, Eric A

PY - 2018/10/1

Y1 - 2018/10/1

N2 - Poly-ADP ribose polymerase 1 (PARP1) is clinically important because of itssynthetic lethality with breast cancer allele 1 and 2 mutations, which are causativefor inherited breast and ovarian cancers. Biochemically, PARP1 is a single-strandedDNA break repair protein that is needed for preserving genomic integrity. In addition,PARP1 has been implicated in a veritable plethora of additional cellular pathwaysand thus its precise contribution(s) to human biology has remained obscure. To helpaddress this deficiency, we utilized gene editing to construct genetically-null PARP1human cancer cells. We found a minor role for PARP1 in an alternative form of DNAdouble-strand break (DSB) repair, but only when these cells were deficient for theclassical form of DSB repair. Despite being proficient for DSB repair, however, cellcycle progression defects and elevated endogenous DNA damage signaling wereobserved. These deficiencies were instead linked to telomere defects, where PARP1-/-cells had short telomeres that co-localized with markers of endogenous DNA damageand were compromised in their ability to escape a telomere-driven crisis. Our datasuggest that while PARP1 does not participate significantly in DNA DSB repair itself,it does prevent the incidence of telomeric DSBs, which, in turn, can drive genomicinstability.

AB - Poly-ADP ribose polymerase 1 (PARP1) is clinically important because of itssynthetic lethality with breast cancer allele 1 and 2 mutations, which are causativefor inherited breast and ovarian cancers. Biochemically, PARP1 is a single-strandedDNA break repair protein that is needed for preserving genomic integrity. In addition,PARP1 has been implicated in a veritable plethora of additional cellular pathwaysand thus its precise contribution(s) to human biology has remained obscure. To helpaddress this deficiency, we utilized gene editing to construct genetically-null PARP1human cancer cells. We found a minor role for PARP1 in an alternative form of DNAdouble-strand break (DSB) repair, but only when these cells were deficient for theclassical form of DSB repair. Despite being proficient for DSB repair, however, cellcycle progression defects and elevated endogenous DNA damage signaling wereobserved. These deficiencies were instead linked to telomere defects, where PARP1-/-cells had short telomeres that co-localized with markers of endogenous DNA damageand were compromised in their ability to escape a telomere-driven crisis. Our datasuggest that while PARP1 does not participate significantly in DNA DSB repair itself,it does prevent the incidence of telomeric DSBs, which, in turn, can drive genomicinstability.

KW - Gene editing

KW - HDR

KW - NHEJ

KW - PARP1

KW - Telomeres

UR - http://www.scopus.com/inward/record.url?scp=85054530765&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054530765&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.26201

DO - 10.18632/oncotarget.26201

M3 - Article

C2 - 30410680

AN - SCOPUS:85054530765

VL - 9

SP - 34821

EP - 34837

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 78

ER -