Genetic determinants of cellular addiction to DNA polymerase theta

Wanjuan Feng; Dennis A. Simpson; Juan Carvajal-Garcia; Brandon A. Price; Rashmi J. Kumar; Lisle E. Mose; Richard D. Wood; Naim Rashid; Jeremy E. Purvis; Joel S. Parker; Dale A. Ramsden; Gaorav P. Gupta

doi:10.1038/s41467-019-12234-1

Genetic determinants of cellular addiction to DNA polymerase theta

Wanjuan Feng, Dennis A. Simpson, Juan Carvajal-Garcia, Brandon A. Price, Rashmi J. Kumar, Lisle E. Mose, Richard D. Wood, Naim Rashid, Jeremy E. Purvis, Joel S. Parker, Dale A. Ramsden, Gaorav P. Gupta

Research output: Contribution to journal › Article › peer-review

92 Scopus citations

Abstract

Polymerase theta (Pol θ, gene name Polq) is a widely conserved DNA polymerase that mediates a microhomology-mediated, error-prone, double strand break (DSB) repair pathway, referred to as Theta Mediated End Joining (TMEJ). Cells with homologous recombination deficiency are reliant on TMEJ for DSB repair. It is unknown whether deficiencies in other components of the DNA damage response (DDR) also result in Pol θ addiction. Here we use a CRISPR genetic screen to uncover 140 Polq synthetic lethal (PolqSL) genes, the majority of which were previously unknown. Functional analyses indicate that Pol θ/TMEJ addiction is associated with increased levels of replication-associated DSBs, regardless of the initial source of damage. We further demonstrate that approximately 30% of TCGA breast cancers have genetic alterations in PolqSL genes and exhibit genomic scars of Pol θ/TMEJ hyperactivity, thereby substantially expanding the subset of human cancers for which Pol θ inhibition represents a promising therapeutic strategy.

Original language	English (US)
Article number	4286
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12234-1
State	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-019-12234-1

Cite this

@article{3aea2b560ce5495db1bffc65067611ad,

title = "Genetic determinants of cellular addiction to DNA polymerase theta",

abstract = "Polymerase theta (Pol θ, gene name Polq) is a widely conserved DNA polymerase that mediates a microhomology-mediated, error-prone, double strand break (DSB) repair pathway, referred to as Theta Mediated End Joining (TMEJ). Cells with homologous recombination deficiency are reliant on TMEJ for DSB repair. It is unknown whether deficiencies in other components of the DNA damage response (DDR) also result in Pol θ addiction. Here we use a CRISPR genetic screen to uncover 140 Polq synthetic lethal (PolqSL) genes, the majority of which were previously unknown. Functional analyses indicate that Pol θ/TMEJ addiction is associated with increased levels of replication-associated DSBs, regardless of the initial source of damage. We further demonstrate that approximately 30% of TCGA breast cancers have genetic alterations in PolqSL genes and exhibit genomic scars of Pol θ/TMEJ hyperactivity, thereby substantially expanding the subset of human cancers for which Pol θ inhibition represents a promising therapeutic strategy.",

author = "Wanjuan Feng and Simpson, {Dennis A.} and Juan Carvajal-Garcia and Price, {Brandon A.} and Kumar, {Rashmi J.} and Mose, {Lisle E.} and Wood, {Richard D.} and Naim Rashid and Purvis, {Jeremy E.} and Parker, {Joel S.} and Ramsden, {Dale A.} and Gupta, {Gaorav P.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-12234-1",

language = "English (US)",

volume = "10",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Genetic determinants of cellular addiction to DNA polymerase theta

AU - Feng, Wanjuan

AU - Simpson, Dennis A.

AU - Carvajal-Garcia, Juan

AU - Price, Brandon A.

AU - Kumar, Rashmi J.

AU - Mose, Lisle E.

AU - Wood, Richard D.

AU - Rashid, Naim

AU - Purvis, Jeremy E.

AU - Parker, Joel S.

AU - Ramsden, Dale A.

AU - Gupta, Gaorav P.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Polymerase theta (Pol θ, gene name Polq) is a widely conserved DNA polymerase that mediates a microhomology-mediated, error-prone, double strand break (DSB) repair pathway, referred to as Theta Mediated End Joining (TMEJ). Cells with homologous recombination deficiency are reliant on TMEJ for DSB repair. It is unknown whether deficiencies in other components of the DNA damage response (DDR) also result in Pol θ addiction. Here we use a CRISPR genetic screen to uncover 140 Polq synthetic lethal (PolqSL) genes, the majority of which were previously unknown. Functional analyses indicate that Pol θ/TMEJ addiction is associated with increased levels of replication-associated DSBs, regardless of the initial source of damage. We further demonstrate that approximately 30% of TCGA breast cancers have genetic alterations in PolqSL genes and exhibit genomic scars of Pol θ/TMEJ hyperactivity, thereby substantially expanding the subset of human cancers for which Pol θ inhibition represents a promising therapeutic strategy.

AB - Polymerase theta (Pol θ, gene name Polq) is a widely conserved DNA polymerase that mediates a microhomology-mediated, error-prone, double strand break (DSB) repair pathway, referred to as Theta Mediated End Joining (TMEJ). Cells with homologous recombination deficiency are reliant on TMEJ for DSB repair. It is unknown whether deficiencies in other components of the DNA damage response (DDR) also result in Pol θ addiction. Here we use a CRISPR genetic screen to uncover 140 Polq synthetic lethal (PolqSL) genes, the majority of which were previously unknown. Functional analyses indicate that Pol θ/TMEJ addiction is associated with increased levels of replication-associated DSBs, regardless of the initial source of damage. We further demonstrate that approximately 30% of TCGA breast cancers have genetic alterations in PolqSL genes and exhibit genomic scars of Pol θ/TMEJ hyperactivity, thereby substantially expanding the subset of human cancers for which Pol θ inhibition represents a promising therapeutic strategy.

UR - http://www.scopus.com/inward/record.url?scp=85072407620&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072407620&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-12234-1

DO - 10.1038/s41467-019-12234-1

M3 - Article

C2 - 31537809

AN - SCOPUS:85072407620

SN - 2041-1723

VL - 10

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4286

ER -

Genetic determinants of cellular addiction to DNA polymerase theta

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this