Fdo1, Fkh1, Fkh2, and the Swi6-Mbp1 MBF complex regulate Mcd1 levels to impact eco1 rad61 cell growth in Saccharomyces cerevisiae.

IF 3.3 3区 生物学 Q2 GENETICS & HEREDITY
Genetics Pub Date : 2024-10-07 DOI:10.1093/genetics/iyae128
Gurvir Singh, Robert V Skibbens
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引用次数: 0

Abstract

Cohesins promote proper chromosome segregation, gene transcription, genomic architecture, DNA condensation, and DNA damage repair. Mutations in either cohesin subunits or regulatory genes can give rise to severe developmental abnormalities (such as Robert Syndrome and Cornelia de Lange Syndrome) and also are highly correlated with cancer. Despite this, little is known about cohesin regulation. Eco1 (ESCO2/EFO2 in humans) and Rad61 (WAPL in humans) represent two such regulators but perform opposing roles. Eco1 acetylation of cohesin during S phase, for instance, stabilizes cohesin-DNA binding to promote sister chromatid cohesion. On the other hand, Rad61 promotes the dissociation of cohesin from DNA. While Eco1 is essential, ECO1 and RAD61 co-deletion results in yeast cell viability, but only within a limited temperature range. Here, we report that eco1rad61 cell lethality is due to reduced levels of the cohesin subunit Mcd1. Results from a suppressor screen further reveals that FDO1 deletion rescues the temperature-sensitive (ts) growth defects exhibited by eco1rad61 double mutant cells by increasing Mcd1 levels. Regulation of MCD1 expression, however, appears more complex. Elevated expression of MBP1, which encodes a subunit of the MBF transcription complex, also rescues eco1rad61 cell growth defects. Elevated expression of SWI6, however, which encodes the Mbp1-binding partner of MBF, exacerbates eco1rad61 cell growth and also abrogates the Mpb1-dependent rescue. Finally, we identify two additional transcription factors, Fkh1 and Fkh2, that impact MCD1 expression. In combination, these findings provide new insights into the nuanced and multi-faceted transcriptional pathways that impact MCD1 expression.

Fdo1、Fkh1、Fkh2 和 Swi6-Mbp1 MBF 复合物调节 Mcd1 水平,从而影响酵母中 eco1 rad61 细胞的生长。
凝聚素能促进染色体的正常分离、基因转录、基因组结构、DNA 聚合和 DNA 损伤修复。凝聚素亚基或调控基因的突变可导致严重的发育异常(如罗伯特综合征和科妮莉亚-德-朗格综合征),而且与癌症高度相关。尽管如此,人们对凝聚素的调控却知之甚少。Eco1(人类中为 ESCO2/EFO2)和 Rad61(人类中为 WAPL)代表了两种此类调控因子,但它们的作用却截然相反。例如,Eco1 在 S 期对凝聚素进行乙酰化可稳定凝聚素与 DNA 的结合,从而促进姐妹染色单体的内聚。另一方面,Rad61 会促进凝聚素与 DNA 的分离。虽然 Eco1 是必不可少的,但 ECO1 和 RAD61 的共同缺失会导致酵母细胞存活,但仅限于有限的温度范围内。在这里,我们报告了 eco1 rad61 细胞致死是由于凝聚素亚基 Mcd1 水平降低所致。抑制剂筛选的结果进一步表明,FDO1 基因缺失可通过提高 Mcd1 的水平来挽救 eco1 rad61 双突变体细胞表现出的温度敏感(ts)生长缺陷。然而,MCD1 的表达调控似乎更为复杂。MBP1 编码 MBF 转录复合物的一个亚基,它的表达增加也能挽救 eco1 rad61 细胞的生长缺陷。然而,编码 MBF 的 Mbp1 结合伙伴的 SWI6 表达量升高会加剧 eco1 rad61 细胞的生长,同时也会削弱 Mpb1 依赖性的拯救作用。最后,我们还发现了另外两个影响 MCD1 表达的转录因子 Fkh1 和 Fkh2。综合这些发现,我们对影响 MCD1 表达的微妙而多方面的转录途径有了新的认识。
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来源期刊
Genetics
Genetics GENETICS & HEREDITY-
CiteScore
6.90
自引率
6.10%
发文量
177
审稿时长
1.5 months
期刊介绍: GENETICS is published by the Genetics Society of America, a scholarly society that seeks to deepen our understanding of the living world by advancing our understanding of genetics. Since 1916, GENETICS has published high-quality, original research presenting novel findings bearing on genetics and genomics. The journal publishes empirical studies of organisms ranging from microbes to humans, as well as theoretical work. While it has an illustrious history, GENETICS has changed along with the communities it serves: it is not your mentor''s journal. The editors make decisions quickly – in around 30 days – without sacrificing the excellence and scholarship for which the journal has long been known. GENETICS is a peer reviewed, peer-edited journal, with an international reach and increasing visibility and impact. All editorial decisions are made through collaboration of at least two editors who are practicing scientists. GENETICS is constantly innovating: expanded types of content include Reviews, Commentary (current issues of interest to geneticists), Perspectives (historical), Primers (to introduce primary literature into the classroom), Toolbox Reviews, plus YeastBook, FlyBook, and WormBook (coming spring 2016). For particularly time-sensitive results, we publish Communications. As part of our mission to serve our communities, we''ve published thematic collections, including Genomic Selection, Multiparental Populations, Mouse Collaborative Cross, and the Genetics of Sex.
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