The role of N-terminus of Plasmodium falciparum ORC1 in telomeric localization and var gene silencing.

Abstract:

:Plasmodium falciparum origin recognition complex 1 (ORC1) protein has been implicated in DNA replication and silencing var gene family. However, the mechanism and the domain structure of ORC1 related to the regulation of var gene family are unknown. Here we show that the unique N-terminus of PfORC1 (PfORC1N(1-238)) is targeted to the nuclear periphery in vivo and this region binds to the telomeric DNA in vitro due to the presence of a leucine heptad repeats. Like PfORC1N(1-238), endogenous full length ORC1, was found to be associated with sub telomeric repeat regions and promoters of various var genes. Additionally, binding and propagation of ORC1 to telomeric and subtelomeric regions was severely compromised in PfSir2 deficient parasites suggesting the dependence of endogenous ORC1 on Sir2 for var gene regulation. This feature is not previously described for Plasmodium ORC1 and contrary to yeast Saccharomyces cerevisiae where ORC function as a landing pad for Sir proteins. Interestingly, the overexpression of ORC1N(1-238) compromises the binding of Sir2 at the subtelomeric loci and var gene promoters consistent with de-repression of some var genes. These results establish role of the N-terminus of PfORC1 in heterochromatin formation and regulation of var gene expression in co-ordination with Sir2 in P. falciparum.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Deshmukh AS,Srivastava S,Herrmann S,Gupta A,Mitra P,Gilberger TW,Dhar SK

doi

10.1093/nar/gks202

subject

Has Abstract

pub_date

2012-07-01 00:00:00

pages

5313-31

issue

12

eissn

0305-1048

issn

1362-4962

pii

gks202

journal_volume

40

pub_type

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