PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage

Stuart G. Jarrett; Erin M.Wolf Horrell; Perry A. Christian; Jillian C. Vanover; Mary C. Boulanger; Yue Zou; John A. D'Orazio

doi:10.1016/j.molcel.2014.05.030

PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage

Stuart G. Jarrett, Erin M.Wolf Horrell, Perry A. Christian, Jillian C. Vanover, Mary C. Boulanger, Yue Zou, John A. D'Orazio

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

75 Scopus citations

Abstract

The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.

Original language	English
Pages (from-to)	999-1011
Number of pages	13
Journal	Molecular Cell
Volume	54
Issue number	6
DOIs	https://doi.org/10.1016/j.molcel.2014.05.030
State	Published - Jun 19 2014

Bibliographical note

Funding Information:
We are indebted to David Fisher, Chris Paumi, Daret St.Clair, and David Cortez and for helpful comments and insight. We thank Carol Beach and Haining Zhu of the University of Kentucky Proteomics Core Facility. This work was supported by the following NIH grants: R01 CA131075, UL1TR000117, ES07266, T32 ES007266, and T32CA165990. We also thank the Drury Pediatric Research Endowed Chair Fund, Wendy Will Case Cancer Research Fund, Markey Cancer Foundation, Children’s Miracle Network, and Jennifer and David Dickens Melanoma Research Foundation.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

Access to Document

10.1016/j.molcel.2014.05.030

Cite this

@article{afbc4adda4f7439a8bcf558d61247b05,

title = "PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage",

abstract = "The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.",

author = "Jarrett, {Stuart G.} and Horrell, {Erin M.Wolf} and Christian, {Perry A.} and Vanover, {Jillian C.} and Boulanger, {Mary C.} and Yue Zou and D'Orazio, {John A.}",

note = "Funding Information: We are indebted to David Fisher, Chris Paumi, Daret St.Clair, and David Cortez and for helpful comments and insight. We thank Carol Beach and Haining Zhu of the University of Kentucky Proteomics Core Facility. This work was supported by the following NIH grants: R01 CA131075, UL1TR000117, ES07266, T32 ES007266, and T32CA165990. We also thank the Drury Pediatric Research Endowed Chair Fund, Wendy Will Case Cancer Research Fund, Markey Cancer Foundation, Children{\textquoteright}s Miracle Network, and Jennifer and David Dickens Melanoma Research Foundation. ",

year = "2014",

month = jun,

day = "19",

doi = "10.1016/j.molcel.2014.05.030",

language = "English",

volume = "54",

pages = "999--1011",

number = "6",

}

TY - JOUR

T1 - PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage

AU - Jarrett, Stuart G.

AU - Horrell, Erin M.Wolf

AU - Christian, Perry A.

AU - Vanover, Jillian C.

AU - Boulanger, Mary C.

AU - Zou, Yue

AU - D'Orazio, John A.

N1 - Funding Information: We are indebted to David Fisher, Chris Paumi, Daret St.Clair, and David Cortez and for helpful comments and insight. We thank Carol Beach and Haining Zhu of the University of Kentucky Proteomics Core Facility. This work was supported by the following NIH grants: R01 CA131075, UL1TR000117, ES07266, T32 ES007266, and T32CA165990. We also thank the Drury Pediatric Research Endowed Chair Fund, Wendy Will Case Cancer Research Fund, Markey Cancer Foundation, Children’s Miracle Network, and Jennifer and David Dickens Melanoma Research Foundation.

PY - 2014/6/19

Y1 - 2014/6/19

N2 - The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.

AB - The melanocortin 1 receptor (MC1R), which signals through cAMP, is a melanocytic transmembrane receptor involved in pigmentation, adaptive tanning, and melanoma resistance. We report MC1R-mediated or pharmacologically-induced cAMP signaling promotes nucleotide excision repair (NER) in a cAMP-dependent protein kinase A (PKA)-dependent manner. PKA directly phosphorylates ataxia telangiectasia and Rad3-related protein (ATR) at Ser435, which actively recruits the key NER protein xeroderma pigmentosum complementation group A (XPA) to sites of nuclear UV photodamage, accelerating clearance of UV-induced photolesions and reducing mutagenesis. Loss of Ser435 within ATR prevents PKA-mediated ATR phosphorylation, disrupts ATR-XPA binding, delays recruitment of XPA to UV-damaged DNA, and elevates UV-induced mutagenesis. This study mechanistically links cAMP-PKA signaling to NER and illustrates potential benefits of cAMP pharmacological rescue to reduce UV mutagenesis in MC1R-defective, melanoma-susceptible individuals.

UR - http://www.scopus.com/inward/record.url?scp=84902650127&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902650127&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2014.05.030

DO - 10.1016/j.molcel.2014.05.030

M3 - Article

C2 - 24950377

AN - SCOPUS:84902650127

SN - 1097-2765

VL - 54

SP - 999

EP - 1011

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

PKA-Mediated Phosphorylation of ATR Promotes Recruitment of XPA to UV-Induced DNA Damage

Abstract

Bibliographical note

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this