Transcriptional Silencing of Centromere Repeats by Heterochromatin Safeguards Chromosome Integrity

Overview

Journal Curr Genet

Specialty Genetics

Date 2019 Apr 19

PMID 30997531

Citations 13

Authors

Takuro Nakagawa

Akiko K Okita

Affiliations

Soon will be listed here.

Abstract

The centromere region of chromosomes consists of repetitive DNA sequences, and is, therefore, one of the fragile sites of chromosomes in many eukaryotes. In the core region, the histone H3 variant CENP-A forms centromere-specific nucleosomes that are required for kinetochore formation. In the pericentromeric region, histone H3 is methylated at lysine 9 (H3K9) and heterochromatin is formed. The transcription of pericentromeric repeats by RNA polymerase II is strictly repressed by heterochromatin. However, the role of the transcriptional silencing of the pericentromeric repeats remains largely unclear. Here, we focus on the chromosomal rearrangements that occur at the repetitive centromeres, and highlight our recent studies showing that transcriptional silencing by heterochromatin suppresses gross chromosomal rearrangements (GCRs) at centromeres in fission yeast. Inactivation of the Clr4 methyltransferase, which is essential for the H3K9 methylation, increased GCRs with breakpoints located in centromeric repeats. However, mutations in RNA polymerase II or the transcription factor Tfs1/TFIIS, which promotes restart of RNA polymerase II following its backtracking, reduced the GCRs that occur in the absence of Clr4, demonstrating that heterochromatin suppresses GCRs by repressing the Tfs1-dependent transcription. We also discuss how the transcriptional restart gives rise to chromosomal rearrangements at centromeres.

Citing Articles

Chromodomain mutation in S. pombe Kat5/Mst1 affects centromere dynamics and DNA repair.

Li T, Petreaca R, Forsburg S PLoS One. 2024; 19(4):e0300732.

PMID: 38662722 PMC: 11045136. DOI: 10.1371/journal.pone.0300732.

Gross Chromosomal Rearrangement at Centromeres.

Xu R, Pan Z, Nakagawa T Biomolecules. 2024; 14(1).

PMID: 38254628 PMC: 10813616. DOI: 10.3390/biom14010028.

Fission yeast Srr1 and Skb1 promote isochromosome formation at the centromere.

Mongia P, Toyofuku N, Pan Z, Xu R, Kinoshita Y, Oki K Commun Biol. 2023; 6(1):551.

PMID: 37237082 PMC: 10219947. DOI: 10.1038/s42003-023-04925-9.

Tfs1, transcription elongation factor TFIIS, has an impact on chromosome segregation affected by pka1 deletion in Schizosaccharomyces pombe.

Takenaka K, Nishioka S, Nishida Y, Kawamukai M, Matsuo Y Curr Genet. 2023; 69(2-3):115-125.

PMID: 37052630 DOI: 10.1007/s00294-023-01268-0.

Human Satellite 1A analysis provides evidence of pericentromeric transcription.

Lopes M, Louzada S, Ferreira D, Verissimo G, Eleuterio D, Gama-Carvalho M BMC Biol. 2023; 21(1):28.

PMID: 36755311 PMC: 9909926. DOI: 10.1186/s12915-023-01521-5.

References

Hansen R, Wijmenga C, Luo P, Stanek A, Canfield T, Weemaes C . The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A. 1999; 96(25):14412-7. PMC: 24450. DOI: 10.1073/pnas.96.25.14412. View

Rea S, Eisenhaber F, OCarroll D, Strahl B, Sun Z, Schmid M . Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature. 2000; 406(6796):593-9. DOI: 10.1038/35020506. View

Lachner M, OCarroll D, Rea S, Mechtler K, Jenuwein T . Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature. 2001; 410(6824):116-20. DOI: 10.1038/35065132. View

Bannister A, Zegerman P, Partridge J, Miska E, Thomas J, Allshire R . Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature. 2001; 410(6824):120-4. DOI: 10.1038/35065138. View

Nakayama J, Rice J, Strahl B, Allis C, Grewal S . Role of histone H3 lysine 9 methylation in epigenetic control of heterochromatin assembly. Science. 2001; 292(5514):110-3. DOI: 10.1126/science.1060118. View

Henikoff S, Ahmad K, Malik H . The centromere paradox: stable inheritance with rapidly evolving DNA. Science. 2001; 293(5532):1098-102. DOI: 10.1126/science.1062939. View

Bernard P, Maure J, Partridge J, Genier S, Javerzat J, Allshire R . Requirement of heterochromatin for cohesion at centromeres. Science. 2001; 294(5551):2539-42. DOI: 10.1126/science.1064027. View

Peters A, OCarroll D, Scherthan H, Mechtler K, Sauer S, Schofer C . Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell. 2001; 107(3):323-37. DOI: 10.1016/s0092-8674(01)00542-6. View

Sun X, Le H, Wahlstrom J, Karpen G . Sequence analysis of a functional Drosophila centromere. Genome Res. 2003; 13(2):182-94. PMC: 420369. DOI: 10.1101/gr.681703. View

10.

Izban M, Luse D . The RNA polymerase II ternary complex cleaves the nascent transcript in a 3'----5' direction in the presence of elongation factor SII. Genes Dev. 1992; 6(7):1342-56. DOI: 10.1101/gad.6.7.1342. View

11.

Osman F, Dixon J, Doe C, Whitby M . Generating crossovers by resolution of nicked Holliday junctions: a role for Mus81-Eme1 in meiosis. Mol Cell. 2003; 12(3):761-74. DOI: 10.1016/s1097-2765(03)00343-5. View

12.

Gravholt C, Friedrich U, Caprani M, Jorgensen A . Breakpoints in Robertsonian translocations are localized to satellite III DNA by fluorescence in situ hybridization. Genomics. 1992; 14(4):924-30. DOI: 10.1016/s0888-7543(05)80113-2. View

13.

Takahashi K, Murakami S, Chikashige Y, Funabiki H, Niwa O, Yanagida M . A low copy number central sequence with strict symmetry and unusual chromatin structure in fission yeast centromere. Mol Biol Cell. 1992; 3(7):819-35. PMC: 275637. DOI: 10.1091/mbc.3.7.819. View

14.

Sadaie M, Iida T, Urano T, Nakayama J . A chromodomain protein, Chp1, is required for the establishment of heterochromatin in fission yeast. EMBO J. 2004; 23(19):3825-35. PMC: 522800. DOI: 10.1038/sj.emboj.7600401. View

15.

Kireeva M, Hancock B, Cremona G, Walter W, Studitsky V, Kashlev M . Nature of the nucleosomal barrier to RNA polymerase II. Mol Cell. 2005; 18(1):97-108. DOI: 10.1016/j.molcel.2005.02.027. View

16.

Kato H, Goto D, Martienssen R, Urano T, Furukawa K, Murakami Y . RNA polymerase II is required for RNAi-dependent heterochromatin assembly. Science. 2005; 309(5733):467-9. DOI: 10.1126/science.1114955. View

17.

Somesh B, Reid J, Liu W, Sogaard T, Erdjument-Bromage H, Tempst P . Multiple mechanisms confining RNA polymerase II ubiquitylation to polymerases undergoing transcriptional arrest. Cell. 2005; 121(6):913-23. DOI: 10.1016/j.cell.2005.04.010. View

18.

Djupedal I, Portoso M, Spahr H, Bonilla C, Gustafsson C, Allshire R . RNA Pol II subunit Rpb7 promotes centromeric transcription and RNAi-directed chromatin silencing. Genes Dev. 2005; 19(19):2301-6. PMC: 1240039. DOI: 10.1101/gad.344205. View

19.

Selmecki A, Forche A, Berman J . Aneuploidy and isochromosome formation in drug-resistant Candida albicans. Science. 2006; 313(5785):367-70. PMC: 1717021. DOI: 10.1126/science.1128242. View

20.

Peng J, Karpen G . H3K9 methylation and RNA interference regulate nucleolar organization and repeated DNA stability. Nat Cell Biol. 2006; 9(1):25-35. PMC: 2819265. DOI: 10.1038/ncb1514. View