Llorens-Agost, Marta ; Ensminger, Michael ; Le, Hang Phuong ; Gawai, Anugrah ; Liu, Jie ; Cruz-García, Andrés ; Bhetawal, Sarita ; Wood, Richard D. ; Heyer, Wolf-Dietrich ; Löbrich, Markus (2021)
POLθ-mediated end joining is restricted by RAD52 and BRCA2 until the onset of mitosis.
In: Nature cell biology, 23 (10)
doi: 10.1038/s41556-021-00764-0
Artikel, Bibliographie
Kurzbeschreibung (Abstract)
BRCA2-mutant cells are defective in homologous recombination, making them vulnerable to the inactivation of other pathways for the repair of DNA double-strand breaks (DSBs). This concept can be clinically exploited but is currently limited due to insufficient knowledge about how DSBs are repaired in the absence of BRCA2. We show that DNA polymerase θ (POLθ)-mediated end joining (TMEJ) repairs DSBs arising during the S phase in BRCA2-deficient cells only after the onset of the ensuing mitosis. This process is regulated by RAD52, whose loss causes the premature usage of TMEJ and the formation of chromosomal fusions. Purified RAD52 and BRCA2 proteins both block the DNA polymerase function of POLθ, suggesting a mechanism explaining their synthetic lethal relationships. We propose that the delay of TMEJ until mitosis ensures the conversion of originally one-ended DSBs into two-ended DSBs. Mitotic chromatin condensation might further serve to juxtapose correct break ends and limit chromosomal fusions.
| Typ des Eintrags: | Artikel |
|---|---|
| Erschienen: | 2021 |
| Autor(en): | Llorens-Agost, Marta ; Ensminger, Michael ; Le, Hang Phuong ; Gawai, Anugrah ; Liu, Jie ; Cruz-García, Andrés ; Bhetawal, Sarita ; Wood, Richard D. ; Heyer, Wolf-Dietrich ; Löbrich, Markus |
| Art des Eintrags: | Bibliographie |
| Titel: | POLθ-mediated end joining is restricted by RAD52 and BRCA2 until the onset of mitosis |
| Sprache: | Englisch |
| Publikationsjahr: | 6 Oktober 2021 |
| Titel der Zeitschrift, Zeitung oder Schriftenreihe: | Nature cell biology |
| Jahrgang/Volume einer Zeitschrift: | 23 |
| (Heft-)Nummer: | 10 |
| DOI: | 10.1038/s41556-021-00764-0 |
| Kurzbeschreibung (Abstract): | BRCA2-mutant cells are defective in homologous recombination, making them vulnerable to the inactivation of other pathways for the repair of DNA double-strand breaks (DSBs). This concept can be clinically exploited but is currently limited due to insufficient knowledge about how DSBs are repaired in the absence of BRCA2. We show that DNA polymerase θ (POLθ)-mediated end joining (TMEJ) repairs DSBs arising during the S phase in BRCA2-deficient cells only after the onset of the ensuing mitosis. This process is regulated by RAD52, whose loss causes the premature usage of TMEJ and the formation of chromosomal fusions. Purified RAD52 and BRCA2 proteins both block the DNA polymerase function of POLθ, suggesting a mechanism explaining their synthetic lethal relationships. We propose that the delay of TMEJ until mitosis ensures the conversion of originally one-ended DSBs into two-ended DSBs. Mitotic chromatin condensation might further serve to juxtapose correct break ends and limit chromosomal fusions. |
| ID-Nummer: | pmid:34616022 |
| Zusätzliche Informationen: | Online ahead of Print |
| Fachbereich(e)/-gebiet(e): | 10 Fachbereich Biologie 10 Fachbereich Biologie > Radiation Biology and DNA Repair |
| Hinterlegungsdatum: | 11 Okt 2021 11:41 |
| Letzte Änderung: | 28 Okt 2021 05:59 |
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