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1.
Nat Cell Biol ; 25(7): 1017-1032, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37414849

RESUMO

Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here we discover a checkpoint-regulated cascade of chromatin signalling that activates the histone methyltransferase EHMT2/G9a to catalyse heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fibre approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favoured by the G9a-dependent exclusion of the H3K9-demethylase JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering single-stranded DNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help in explaining chemotherapy resistance and poor prognosis observed in patients with cancer displaying elevated levels of G9a/H3K9me3.


Assuntos
Heterocromatina , Histonas , Humanos , Histonas/genética , Histonas/metabolismo , Heterocromatina/genética , Cromatina/genética , Montagem e Desmontagem da Cromatina , Replicação do DNA , Antígenos de Histocompatibilidade , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética
3.
Nat Cell Biol ; 23(6): 608-619, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34108662

RESUMO

Correct transcription is crucial for life. However, DNA damage severely impedes elongating RNA polymerase II, causing transcription inhibition and transcription-replication conflicts. Cells are equipped with intricate mechanisms to counteract the severe consequence of these transcription-blocking lesions. However, the exact mechanism and factors involved remain largely unknown. Here, using a genome-wide CRISPR-Cas9 screen, we identified the elongation factor ELOF1 as an important factor in the transcription stress response following DNA damage. We show that ELOF1 has an evolutionarily conserved role in transcription-coupled nucleotide excision repair (TC-NER), where it promotes recruitment of the TC-NER factors UVSSA and TFIIH to efficiently repair transcription-blocking lesions and resume transcription. Additionally, ELOF1 modulates transcription to protect cells against transcription-mediated replication stress, thereby preserving genome stability. Thus, ELOF1 protects the transcription machinery from DNA damage via two distinct mechanisms.


Assuntos
Dano ao DNA , Reparo do DNA , Instabilidade Genômica , Fator 1 de Elongação de Peptídeos/metabolismo , Elongação da Transcrição Genética , Sistemas CRISPR-Cas , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Evolução Molecular , Células HCT116 , Humanos , Fator 1 de Elongação de Peptídeos/genética , RNA Polimerase II/metabolismo , Fator de Transcrição TFIIH/genética , Fator de Transcrição TFIIH/metabolismo , Ubiquitinação
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