Dr Goedele N Maertens

Polycomb Group Proteins, INK4a, and DNA damage.

Epigenetic regulation, or the heritable changes made to chromatin without mutating the DNA sequence, is an intricately regulated process. Trithorax Group Proteins, involved in marking the chromatin for active transcription are counteracted by Polycomb Group Proteins (PcG). PcG, originally identified in Drosophila, function in at least two distinct complexes; Polycomb Repressive Complex 2 (PRC2) sets the trimethyl mark on Lys 27 of Histone H3 (H3K27me3). This mark recruits the maintenance or PRC1 complex which ubiquitinates  Lys119 of histone H2A (uH2A) (Cao R. et al, 2005, Wang H. et al, 2004, Elderkin S et al, 2007). In addition to the regulation of housekeeping genes, PcG have also been shown to regulate the INK4a/ARF tumour suppressor locus  (Gil J. et al, 2004). Moreover, we've recently shown that multiple PRC1 complexes occupy and repress INK4a/ARF (Maertens G., et al 2010). The INK4a/ARF locus plays a key role in cellular senescence (Reviewed in Gil J. and Peters G. 2006, Sharpless NE, 2005); the state of irreversible growth arrest, which is an essential mechanism that protects multi-cellular organisms against unsolicited cell proliferation. Although until recently the role of PRC1 in oncogenesis was ascribed mostly to its role in INK4a repression, there is now evidence that PRC1 is also involved in DNA damage repair (Reviewed in Gieni RS et al, 2011), a pathway often misregulated in cancer. How this process is regulated and what the role of the PcG proteins is at these sites is yet largely unknown. We are investigating this using a variety of techniques (laser induced DNA damage and confocal microscopy, chromatin immunoprecipitation,...). In addition, we are taking a closer look at how different PRC1 components interact within the complex, using structural biology techniques.

Interaction between Retroviral integrase and the host-cellular machinery.

To establish successful infection, a retrovirus must integrate a copy of its genome into a host cell chromosome. This reaction is catalyzed by the viral enzyme integrase (IN). A tetramer of IN binds and synapses viral DNA ends, forming a highly stable complex, referred to as intasome (Hare S. et al, 2010).  After transfer to the nucleus, IN joins the 3’ ends of viral DNA to host cell chromosomal DNA (Maertens G. et al, 2010). A stable provirus is established after the repair of single-stranded gaps initially flanking the integrated viral DNA. While the integration reaction ("cutting and pasting" of the viral cDNA copy into the host chromatin) is catalyzed by virally encoded IN, the targeting of the pre-integration complex (PIC) to the site of integration and the post-integration events to establish a stable provirus, are mediated by the interaction with host factors. Lentiviral INs (such as Human Immunodeficiency Virus type 1) depend on the interaction with LEDGF/p75, which targets the PIC to actively transcribed chromatin (Reviewed in Engelman A. and Cherepanov P. 2008). We are interested in identifying and characterizing host-factors for lenti- and other retroviral INs involved in targeting of integration and post-integration repair.

Research themes.

* Role of PRC1 and PRC1 interacting proteins in DNA damage repair

* Structural biology of PcG complexes

* Interaction of retroviral INs with the host cellular machinery

Recent publications.

1.         Cherepanov, P., Maertens, G.N., and Hare, S. Structural Insights into the Retroviral DNA integration apparatus. (2011) Current Opinion in Structural Biology, 21, 249-256.

2.         Maertens, G.N., Hare, S., and Cherepanov, P. (2010) The mechanism of retroviral integration through X-ray structures of its key intermediates. Nature, 468:326-329.

3.         Maertens, G.N., El Messaoudi-Aubert, S., Elderkin S., Hiom, K., and Peters, G. (2010) Ubiquitin-specific proteases 7 and 11 modulate Polycomb regulation of the INK4a tumour suppressor. EMBO J., 29:2553-65.

4.         El Messaoudi-Aubert, S., Nicholls, J., Maertens, G.N., Bernstein E., and Peters G. (2010) Role for the MOV10 RNA helicase in Polycomb-mediated repression of the INK4a tumor suppressor. Nat. Struct. Mol. Biol., 17:862-868.

5.         Maertens, G.N., El Messaoudi-Aubert, S., Racek, T., Stock, J. K., Nicholls, J., Rodriguez-Niedenfuhr, M., Gil, J., Peters, G. (2009) Multiple PRC1 complexes are directly involved in repression of the INK4A-ARF tumor suppressor locus. PLoS One, 4 (7):e6380.

6.         Barradas, M. Anderton, E., Acosta, J.C., Li, S., Banito, A., Rodriguez-Niedenfuhr, M., Maertens, G., Back, M., Zhou, M.M., Walsh, M.J., Peters, G., and Gil, J. (2009) Histone demethylase JMJD3 contributes to epigenetic control of INK4A/ARF by oncogenic RAS. Genes. Dev., 23:1177-1182.

7.         Elderkin, S., Maertens, G.N., Endoh, M., Mallery, D., Morrice, N., Koseki, H., Peters, G., Brockdorff, N., and Hiom, K. (2007) A phosphorylated form of Mel-18 targets the Ring1B histone H2A ubiquitin ligase to chromatin. Mol. Cell, 28(1):107-120.