L3MBTL1 polycomb protein, a candidate tumor suppressor in del(20q12) myeloid disorders, is essential for genome stability

Nadia Gurvich, Fabiana Perna, Andrea Farina, Francesca Voza, Silvia Menendez, Jerard Hurwitz, Stephen D. Nimer

Research output: Contribution to journalArticle

59 Scopus citations

Abstract

The l3mbtl1 gene is located on the long arm of chromosome 20 (q12), within a region commonly deleted in several myeloid malignancies. L3MBTL1 is a human homolog of the Drosophila polycomb L(3)MBT tumor suppressor protein and thus a candidate tumor suppressor in del(20q12) myeloid disorders. We used the loss-of-function approach to explore the possible tumor suppressive mechanism of L3MBTL1 and found that depletion of L3MBTL1 from human cells causes replicative stress, DNA breaks, activation of the DNA damage response, and genomic instability. L3MBTL1 interacts with Cdc45, MCM2-7 and PCNA, components of the DNA replication machinery, and is required for normal replication fork progression, suggesting that L3MBTL1 causes DNA damage, at least in part, by perturbing DNA replication. An activated DNA damage response and genomic instability are common features in tumorigenesis and a consequence of overexpression of many oncogenes. We propose that the loss of L3MBTL1 contributes to the development of 20q- hematopoietic malignancies by inducing replicative stress, DNA damage, and genomic instability.

Original languageEnglish (US)
Pages (from-to)22552-22557
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number52
DOIs
StatePublished - Dec 28 2010

Keywords

  • Chromatin reader
  • H4K20me1/2 binding protein

ASJC Scopus subject areas

  • General

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