Tài liệu Báo cáo khoa học: DNA methylation-mediated nucleosome dynamics and oncogenic Ras signaling

REVIEW ARTICLE

DNA methylation-mediated nucleosome dynamics and

oncogenic Ras signaling

Insights from FAS, FAS ligand and RASSF1A

Samir K. Patra1,* and Moshe Szyf2

1 Cancer Epigenetics Research, Kalyani, India

2 Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada

DNA methylation and chromatin modification and

remodeling are currently center stage in studies of the

epigenetic regulation of genome function in normal

physiology, disease states and development [1–25]. Sev￾eral isoforms of enzymes catalyzing both DNA and

histone modifications have been characterized. Con￾comitant with differentiation, cell-type-specific patterns

of DNA methylation and histone modification are gen￾erated and are believed to program cell-type-specific

physiological functions, including memory formation

in neurons [2,18,20]. These elaborate epigenetic

programs may be difficult to reverse and rebuild

during animal cloning procedures, because the signals

and mechanisms for gene-specific hypermethylation

and global demethylation patterns are not completely

understood [2]. In eukaryotes, the chromatin is orga￾nized as euchromatin and heterochromatin. Euchroma￾tin encompasses the majority of single-copy genes, it

replicates during early S phase and contains acetylated

histones. Heterochromatin is composed of long

Keywords

apoptosis; cancer; DNA methylation;

epigenetics; FAS; FAS ligand; H-Ras; K-Ras;

nucleosome dynamics; RASSF1A

Correspondence

S. K. Patra, Cancer Epigenetics Research,

Kalyani (B-7 ⁄ 183), Nadia, West Bengal, India

Fax: +91 332 582 8460

Tel: +91 943 206 0602

E-mail: [email protected]

*Present address

Division of Biochemistry, Department of

Experimental Medicine, University of Parma,

Italy

(Received 5 June 2008, revised 8 August

2008, accepted 22 August 2008)

doi:10.1111/j.1742-4658.2008.06658.x

Cytosine methylation at the 5-carbon position is the only known stable

base modification found in the mammalian genome. The organization and

modification of chromatin is a key factor in programming gene expression

patterns. Recent findings suggest that DNA methylation at the junction of

transcription initiation and elongation plays a critical role in suppression

of transcription. This effect is mechanistically mediated by the state of

chromatin modification. DNA methylation attracts binding of methyl￾CpG-binding domain proteins that trigger repression of transcription,

whereas DNA demethylation facilitates transcription activation. Under￾standing the rules that guide differential gene expression, as well as tran￾scription dynamics and transcript abundance, has proven to be a taxing

problem for molecular biologists and oncologists alike. The use of novel

molecular modeling methods is providing exciting insights into the chal￾lenging problem of how methylation mediates chromatin dynamics. New

data implicate lipid rafts as the coordinators of signals emanating from the

cell membrane and are converging on the mechanisms linking DNA meth￾ylation and chromatin dynamics. This review focuses on some of these

recent advances and uses lipid-raft-facilitated Ras signaling as a paradigm

for understanding DNA methylation, chromatin dynamics and apoptosis.

Abbreviations

aSMAase, acid sphingomyelinase; DISC, death-inducing signaling complex; DNMTs, DNA methyltransferases; FADD, FAS-associated death

domain; FASL, FAS ligand; gld, generalized lymphoproliferative disorder; lpr, lymphoproliferative disorder; MAPK, mitogen activated protein

kinase; MBD, methyl-CpG-binding domain proteins; MGMT, O6-methylguanine methyltransferase; RESE, Ras epigenetic silencing effectors;

TNF, tumor necrosis factor.

FEBS Journal 275 (2008) 5217–5235 ª 2008 The Authors Journal compilation ª 2008 FEBS 5217