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Home page > Research Groups > Marta RADMAN-LIVAJA - Chromatin and DNA Replication

Marta RADMAN-LIVAJA - Chromatin and DNA Replication

The smallest repeating subunit of chromatin- the eukaryotic DNA packaging system- is the nucleosome: a 147 bp DNA segment wrapped 1.65 turns around a histone octamer core, consisting of one H3/H4 tetramer and two H2A/H2B dimers. Genes carry a “chromatin footprint” consisting of specific nucleosome positions, histone variant replacements of canonical histones and posttranslational histone modifications that, to a certain degree, reflect the gene’s activation state. For instance, the chromatin structure of an actively transcribed budding yeast gene promoter is characterized by two well positioned nucleosomes- the -1 and +1 nucleosomes- separated by a 150bp nucleosome free region (NFR), and the transcription start site is located about 20bp downstream of the 5’ end of the +1 nucleosome. Such chromatin “signatures” have to be disrupted during genome replication, as nucleosomes are disassembled ahead of the replication fork and are reassembled in its wake.

Chromatin (re)assembly is a fundamental cellular process intimately linked to the maintenance of genome integrity and transcriptional programs. Understanding the effect of DNA replication on histone protein dynamics is also a prerequisite for understanding the potential for chromatin structure to carry epigenetic information. While epigenetic inheritance of chromatin structure components is, in theory, widely accepted as the driver of epigenetic phenomena, which are thought to influence anything from cellular differentiation and cancer formation to the role of early developmental insults in later predispositions to disease, chromatin inheritance per se has only been experimentally demonstrated for a few specific cases.

Not much is known about histone “inheritance” beyond the facts that bulk maternal histones distribute equally among the daughter strands and are diluted two-fold after replication by the binding of newly synthesized “unmarked” histones, and that the majority of H3/H4 tetramers do not split before reassembly on daughter DNA strands. We have shown previously that maternal nucleosomes stay on average within 400bp of their original binding site, once they are reassembled on DNA after the replication fork has passed through, implying that any potentially heritable chromatin encoded information, has to be inherited in 1kb blocs, as smaller nucleosome domains would rapidly be diluted by new nucleosomes and would quickly move away from their maternal DNA binding site.

My group will be developing systems for directly measuring movements of histones and chromatin regulators during genomic replication in S.cerevisiae to determine, on a genomic scale, how chromatin states survive the perturbations associated with replication. This will allow us to address questions such as: how the spreading of maternal nucleosomes following replication differs from locus to locus, whether leading and lagging strand replication have different effects on nucleosome positioning and maternal nucleosome distribution, how are posttranslational histone marks and chromatin binding proteins redistributed after the passage of the replication fork and how is the pre-replication chromatin footprint re-established.

Recent publications :

1. Sarkar D, Radman-Livaja M, Landy A (2001). "The small DNA binding domain of lambda integrase is a context-sensitive modulator of recombinase functions." EMBO J 20(5): 1203-12.

2. Nunes-Duby SE, Radman-Livaja M, Kuimelis RG, Pearline RV, McLaughlin LW, Landy A (2002). "Gamma integrase complementation at the level of DNA binding and complex formation." J Bacteriol 184(5): 1385-94.

3. Radman-Livaja M, Shaw C, Azaro M, Biswas T, Ellenberger T, Landy A (2003). "Arm sequences contribute to the architecture and catalytic function of a lambda integrase-Holliday junction complex." Molecular cell 11(3): 783-94.

4. Biswas T, Aihara H, Radman-Livaja M, Filman D, Landy A, Ellenberger T (2005). "A structural basis for allosteric control of DNA recombination by lambda integrase." Nature 435(7045): 1059-66.

5. Hazelbaker D, Radman-Livaja M, Landy A (2005). "Receipt of the C-terminal tail from a neighboring lambda Int protomer allosterically stimulates Holliday junction resolution." J Mol Biol 351(5): 948-55.

6. Lee SY, Radman-Livaja M, Warren D, Aihara H, Ellenberger T, Landy A (2005). "Non-equivalent interactions between amino-terminal domains of neighboring lambda integrase protomers direct Holliday junction resolution." J Mol Biol 345(3): 475-85.

7. Radman-Livaja M, Biswas T, Mierke D, Landy A (2005). "Architecture of recombination intermediates visualized by in-gel FRET of lambda integrase-Holliday junction-arm DNA complexes." Proceedings of the National Academy of Sciences of the United States of America 102(11): 3913-20.

8. Radman-Livaja M, Biswas T, Ellenberger T, Landy A, Aihara H (2006). "DNA arms do the legwork to ensure the directionality of lambda site-specific recombination." Curr Opin Struct Biol 16(1): 42-50.

9. Sun X, Mierke DF, Biswas T, Lee SY, Landy A, Radman-Livaja M (2006). "Architecture of the 99 bp DNA-six-protein regulatory complex of the lambda att site." Molecular cell 24(4): 569-80.

10. Radman-Livaja M, Liu CL, Friedman N, Schreiber SL, Rando OJ (2010). "Replication and active demethylation represent partially overlapping mechanisms for erasure of H3K4me3 in budding yeast." PLoS Genet 6(2): e1000837.

11. Radman-Livaja M, Rando OJ (2010). "Nucleosome positioning: how is it established, and why does it matter?" Dev Biol 339(2): 258-66.

12. Radman-Livaja M, Ruben G, Weiner A, Friedman N, Kamakaka R, Rando OJ (2011). "Dynamics of Sir3 spreading in budding yeast: secondary recruitment sites and euchromatic localization." EMBO J 30(6): 1012-26.

13. Radman-Livaja M, Verzijlbergen KF, Weiner A, van Welsem T, Friedman N, Rando OJ, van Leeuwen F (2011). "Patterns and mechanisms of ancestral histone protein inheritance in budding yeast." PLoS Biol 9(6): e1001075.

14. Radman-Livaja M, Quan TK, Valenzuela L, Armstrong JA, van Welsem T, Kim T, Lee LJ, Buratowski S, van Leeuwen F, Rando OJ, Hartzog GA (2012). "A key role for Chd1 in histone H3 dynamics at the 3’ ends of long genes in yeast." PLoS Genet 8(7): e1002811.

15. Watanabe S, Radman-Livaja M, Rando OJ, Peterson CL (2013). "A histone acetylation switch regulates H2A.Z deposition by the SWR-C remodeling enzyme." Science 340(6129): 195-9.

Institut de Génétique Moléculaire de Montpellier
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