Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F20%3A00523160" target="_blank" >RIV/61388963:_____/20:00523160 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.nature.com/articles/s41586-020-2059-5" target="_blank" >https://www.nature.com/articles/s41586-020-2059-5</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41586-020-2059-5" target="_blank" >10.1038/s41586-020-2059-5</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

Popis výsledku v původním jazyce

Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption(1). Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers(1,2). 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 cancer(3,4). The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells(5-7). 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.

Název v anglickém jazyce

Alcohol-derived DNA crosslinks are repaired by two distinct mechanisms

Popis výsledku anglicky

Acetaldehyde is a highly reactive, DNA-damaging metabolite that is produced upon alcohol consumption(1). Impaired detoxification of acetaldehyde is common in the Asian population, and is associated with alcohol-related cancers(1,2). 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 cancer(3,4). The combined inactivation of acetaldehyde detoxification and the FA pathway induces mutation, accelerates malignancies and causes the rapid attrition of blood stem cells(5-7). 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nature

ISSN

0028-0836

e-ISSN

—

Svazek periodika

579

Číslo periodika v rámci svazku

7800

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

6

Strana od-do

603-608

Kód UT WoS článku

000518098200005

EID výsledku v databázi Scopus

2-s2.0-85081583872