The DNA translocase activity of FANCM protects stalled replication forks

Autor: Andrew N. Blackford, Stephen C. West, Rebekka A. Schwab, Wojciech Niedzwiedz, Jadwiga Nieminuszczy, Andrew J. Deans
Rok vydání: 2012
Předmět:
DNA Replication
congenital
hereditary
and neonatal diseases and abnormalities
DNA Repair
Cell Cycle Proteins
Eukaryotic DNA replication
Ataxia Telangiectasia Mutated Proteins
Protein Serine-Threonine Kinases
Biology
Models
Biological
Cell Line
DNA replication factor CDT1
Gene Knockout Techniques
Replication factor C
Control of chromosome duplication
hemic and lymphatic diseases
Genetics
Animals
Humans
DNA Breaks
Double-Stranded
FANCM
RNA
Small Interfering
Homologous Recombination
Molecular Biology
Replication protein A
Genetics (clinical)
Tumor Suppressor Proteins
DNA Helicases
Intracellular Signaling Peptides and Proteins
nutritional and metabolic diseases
General Medicine
DNA Replication Fork
DNA-Binding Proteins
Fanconi Anemia
HEK293 Cells
Nucleotide Transport Proteins
Cancer research
biology.protein
Origin recognition complex
Tumor Suppressor p53-Binding Protein 1
HeLa Cells
Zdroj: Human Molecular Genetics. 21:2005-2016
ISSN: 1460-2083
0964-6906
Popis: FANCM is the most highly conserved protein within the Fanconi anaemia (FA) tumour suppressor pathway. However, although FANCM contains a helicase domain with translocase activity, this is not required for its role in activating the FA pathway. Instead, we show here that FANCM translocaseactivity is essential for promoting replication fork stability. We demonstrate that cells expressing translocase-defective FANCM show altered global replication dynamics due to increased accumulation of stalled forks that subsequently degenerate into DNA double-strand breaks, leading to ATM activation, CTBP-interacting protein (CTIP)-dependent end resection and homologous recombination repair. Accordingly, abrogation of ATM or CTIP function in FANCM-deficient cells results in decreased cell survival. We also found that FANCM translocase activity protects cells from accumulating 53BP1-OPT domains, which mark lesions resulting from problems arising during replication. Taken together, these data show that FANCM plays an essential role in maintaining chromosomal integrity by promoting the recovery of stalled replication forks and hence preventing tumourigenesis.
Databáze: OpenAIRE
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