Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

Michael R Hodskinson; Alice Bolner; Koichi Sato; Ashley N Kamimae-Lanning; Koos Rooijers; Merlijn Witte; Mohan Mahesh; Jan Silhan; Maya Petek; David M Williams; Jop Kind; Jason W Chin; Ketan J Patel; Puck Knipscheer

doi:10.1038/s41586-020-2059-5

Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

Michael R Hodskinson, Alice Bolner, Koichi Sato, Ashley N Kamimae-Lanning, Koos Rooijers, Merlijn Witte, Mohan Mahesh, Jan Silhan, Maya Petek, David M Williams, Jop Kind, Jason W Chin, Ketan J Patel, Puck Knipscheer

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

Abstract

Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption1. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers1,2. Cells are protected against acetaldehyde-induced damage by DNA crosslink repair, which when impaired causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer3,4. The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells5-7. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question. Here we generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. We find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision-analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks. The second repair mechanism requires replication fork convergence, but does not involve DNA incisions-instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism.

Original language	English
Pages (from-to)	603-608
Number of pages	6
Journal	Nature
Volume	579
Issue number	7800
DOIs	https://doi.org/10.1038/s41586-020-2059-5
Publication status	Published - Mar 2020

Access to Document

10.1038/s41586-020-2059-5

Cite this

@article{dd7596c140f448a9b685db7b3ff61efe,

title = "Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms",

abstract = "Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption1. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers1,2. Cells are protected against acetaldehyde-induced damage by DNA crosslink repair, which when impaired causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer3,4. The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells5-7. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question. Here we generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. We find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision-analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks. The second repair mechanism requires replication fork convergence, but does not involve DNA incisions-instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism.",

author = "Hodskinson, {Michael R} and Alice Bolner and Koichi Sato and Kamimae-Lanning, {Ashley N} and Koos Rooijers and Merlijn Witte and Mohan Mahesh and Jan Silhan and Maya Petek and Williams, {David M} and Jop Kind and Chin, {Jason W} and Patel, {Ketan J} and Puck Knipscheer",

year = "2020",

month = mar,

doi = "10.1038/s41586-020-2059-5",

language = "English",

volume = "579",

pages = "603--608",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7800",

}

TY - JOUR

T1 - Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

AU - Hodskinson, Michael R

AU - Bolner, Alice

AU - Sato, Koichi

AU - Kamimae-Lanning, Ashley N

AU - Rooijers, Koos

AU - Witte, Merlijn

AU - Mahesh, Mohan

AU - Silhan, Jan

AU - Petek, Maya

AU - Williams, David M

AU - Kind, Jop

AU - Chin, Jason W

AU - Patel, Ketan J

AU - Knipscheer, Puck

PY - 2020/3

Y1 - 2020/3

N2 - Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption1. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers1,2. Cells are protected against acetaldehyde-induced damage by DNA crosslink repair, which when impaired causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer3,4. The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells5-7. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question. Here we generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. We find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision-analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks. The second repair mechanism requires replication fork convergence, but does not involve DNA incisions-instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism.

AB - Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption1. Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers1,2. Cells are protected against acetaldehyde-induced damage by DNA crosslink repair, which when impaired causes Fanconi anaemia (FA), a disease resulting in failure to produce blood cells and a predisposition to cancer3,4. The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells5-7. However, the nature of the DNA damage induced by acetaldehyde and how this is repaired remains a key question. Here we generate acetaldehyde-induced DNA interstrand crosslinks and determine their repair mechanism in Xenopus egg extracts. We find that two replication-coupled pathways repair these lesions. The first is the FA pathway, which operates using excision-analogous to the mechanism used to repair the interstrand crosslinks caused by the chemotherapeutic agent cisplatin. However, the repair of acetaldehyde-induced crosslinks results in increased mutation frequency and an altered mutational spectrum compared with the repair of cisplatin-induced crosslinks. The second repair mechanism requires replication fork convergence, but does not involve DNA incisions-instead the acetaldehyde crosslink itself is broken. The Y-family DNA polymerase REV1 completes repair of the crosslink, culminating in a distinct mutational spectrum. These results define the repair pathways of DNA interstrand crosslinks caused by an endogenous and alcohol-derived metabolite, and identify an excision-independent mechanism.

U2 - 10.1038/s41586-020-2059-5

DO - 10.1038/s41586-020-2059-5

M3 - Article

C2 - 32132710

SN - 0028-0836

VL - 579

SP - 603

EP - 608

JO - Nature

JF - Nature

IS - 7800

ER -

Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

Abstract

Access to Document

Fingerprint

Cite this