scholarly journals FANCI plays an essential role in spermatogenesis and regulates meiotic histone methylation

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Lan Xu ◽  
Weiwei Xu ◽  
Duan Li ◽  
Xiaoxia Yu ◽  
Fei Gao ◽  
...  
Keyword(s):  
Histone Methylation ◽  
Molecular Basis ◽  
Essential Role ◽  
Seminiferous Tubules ◽  
Nonobstructive Azoospermia ◽  
Core Complex ◽  
Interstrand Cross Links ◽  
Cross Links ◽  
Underlying Mechanisms

AbstractFANCI is an essential component of Fanconi anemia pathway, which is responsible for the repair of DNA interstrand cross-links (ICLs). As an evolutionarily related partner of FANCD2, FANCI functions together with FANCD2 downstream of FA core complex. Currently, growing evidences showed that the essential role of FA pathway in male fertility. However, the underlying mechanisms for FANCI in regulating spermatogenesis remain unclear. In the present study, we found that the male Fanci−/− mice were sterile and exhibited abnormal spermatogenesis, including massive germ cell apoptosis in seminiferous tubules and dramatically decreased number of sperms in epididymis. Besides, FANCI deletion impaired maintenance of undifferentiated spermatogonia. Further investigation indicated that FANCI was essential for FANCD2 foci formation and regulated H3K4 and H3K9 methylation on meiotic sex chromosomes. These findings elucidate the role and mechanism of FANCI during spermatogenesis in mice and provide new insights into the etiology and molecular basis of nonobstructive azoospermia.

scholarly journals From Capsids to Complexes: Expanding the Role of TRIM5α in the Restriction of Divergent RNA Viruses and Elements

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 446
Author(s):  
Kevin M. Rose ◽  
Stephanie J. Spada ◽  
Rebecca Broeckel ◽  
Kristin L. McNally ◽  
Vanessa M. Hirsch ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Molecular Basis ◽  
Human Population ◽  
Rna Viruses ◽  
Arms Race ◽  
Innate Immune ◽  
Immunodeficiency Virus ◽  
Underlying Mechanisms ◽  
Hiv 1

An evolutionary arms race has been ongoing between retroviruses and their primate hosts for millions of years. Within the last century, a zoonotic transmission introduced the Human Immunodeficiency Virus (HIV-1), a retrovirus, to the human population that has claimed the lives of millions of individuals and is still infecting over a million people every year. To counteract retroviruses such as this, primates including humans have evolved an innate immune sensor for the retroviral capsid lattice known as TRIM5α. Although the molecular basis for its ability to restrict retroviruses is debated, it is currently accepted that TRIM5α forms higher-order assemblies around the incoming retroviral capsid that are not only disruptive for the virus lifecycle, but also trigger the activation of an antiviral state. More recently, it was discovered that TRIM5α restriction is broader than previously thought because it restricts not only the human retroelement LINE-1, but also the tick-borne flaviviruses, an emergent group of RNA viruses that have vastly different strategies for replication compared to retroviruses. This review focuses on the underlying mechanisms of TRIM5α-mediated restriction of retroelements and flaviviruses and how they differ from the more widely known ability of TRIM5α to restrict retroviruses.

scholarly journals EPC1/TIP60-Mediated Histone Acetylation Facilitates Spermiogenesis in Mice

2017 ◽  
Vol 37 (19) ◽  
Author(s):  
Yixin Dong ◽  
Kyo-ichi Isono ◽  
Kazuyuki Ohbo ◽  
Takaho A. Endo ◽  
Osamu Ohara ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Germ Cells ◽  
Essential Role ◽  
Critical Role ◽  
Male Germ Cells ◽  
Genetic Ablation ◽  
Histone Hyperacetylation ◽  
Critical Components ◽  
Underlying Mechanisms

ABSTRACT Global histone hyperacetylation is suggested to play a critical role for replacement of histones by transition proteins and protamines to compact the genome during spermiogenesis. However, the underlying mechanisms for hyperacetylation-mediated histone replacement remains poorly understood. Here, we report that EPC1 and TIP60, two critical components of the mammalian nucleosome acetyltransferase of H4 (NuA4) complexes, are coexpressed in male germ cells. Strikingly, genetic ablation of either Epc1 or Tip60 disrupts hyperacetylation and impairs histone replacement, in turn causing aberrant spermatid development. Taking these observations together, we reveal an essential role of the NuA4 complexes for histone hyperacetylation and subsequent compaction of the spermatid genome.

scholarly journals Structural insight into FANCI–FANCD2 monoubiquitination

2020 ◽  
Vol 64 (5) ◽  
pp. 807-817 ◽  
Author(s):  
Landing Li ◽  
Winnie Tan ◽  
Andrew J. Deans
Keyword(s):  
Dna Repair ◽  
Bone Marrow Failure ◽  
Core Complex ◽  
Bone Marrow Failure Syndrome ◽  
Cryo Electron Microscopy ◽  
Ubiquitin Ligase Complex ◽  
Interstrand Cross Links ◽  
Cross Links ◽  
Made In

Abstract The Fanconi anemia (FA) pathway coordinates a faithful repair mechanism for DNA damage that blocks DNA replication, such as interstrand cross-links. A key step in the FA pathway is the conjugation of ubiquitin on to FANCD2 and FANCI, which is facilitated by a large E3 ubiquitin ligase complex called the FA core complex. Mutations in FANCD2, FANCI or FA core complex components cause the FA bone marrow failure syndrome. Despite the importance of these proteins to DNA repair and human disease, our molecular understanding of the FA pathway has been limited due to a deficit in structural studies. With the recent development in cryo-electron microscopy (EM), significant advances have been made in structural characterization of these proteins in the last 6 months. These structures, combined with new biochemical studies, now provide a more detailed understanding of how FANCD2 and FANCI are monoubiquitinated and how DNA repair may occur. In this review, we summarize these recent advances in the structural and molecular understanding of these key components in the FA pathway, compare the activation steps of FANCD2 and FANCI monoubiquitination and suggest molecular steps that are likely to be involved in regulating its activity.

scholarly journals Processing of a Psoralen DNA Interstrand Cross-link by XPF-ERCC1 Complex in Vitro

2007 ◽  
Vol 283 (3) ◽  
pp. 1275-1281 ◽  
Author(s):  
Laura A. Fisher ◽  
Mika Bessho ◽  
Tadayoshi Bessho
Keyword(s):  
Strand Break ◽  
Double Strand Break ◽  
Dependent Manner ◽  
Cross Link ◽  
Interstrand Cross Links ◽  
Cross Links ◽  
The Cross ◽  
Stalled Fork

The processing of stalled forks caused by DNA interstrand cross-links (ICLs) has been proposed to be an important step in initiating mammalian ICL repair. To investigate a role of the XPF-ERCC1 complex in this process, we designed a model substrate DNA with a single psoralen ICL at a three-way junction (Y-shaped DNA), which mimics a stalled fork structure. We found that the XPF-ERCC1 complex makes an incision 5′ to a psoralen lesion on Y-shaped DNA in a damage-dependent manner. Furthermore, the XPF-ERCC1 complex generates an ICL-specific incision on the 3′-side of an ICL. The ICL-specific 3′-incision, along with the 5′-incision, on the cross-linked Y-shaped DNA resulted in the separation of the two cross-linked strands (the unhooking of the ICL) and the induction of a double strand break near the cross-linked site. These results implicate the XPF-ERCC1 complex in initiating ICL repair by unhooking the ICL, which simultaneously induces a double strand break at a stalled fork.

scholarly journals Structural basis for COMPASS recognition of an H2B-ubiquitinated nucleosome

2019 ◽  
Author(s):  
Evan J. Worden ◽  
Xiangbin Zhang ◽  
Cynthia Wolberger
Keyword(s):  
Histone Methylation ◽  
Structural Basis ◽  
Structural Rearrangements ◽  
H3k4 Methylation ◽  
Core Complex ◽  
Histone H2b ◽  
Protein Core ◽  
The Face ◽  
Histone H3k4

ABSTRACTMethylation of histone H3K4 is a hallmark of actively transcribed genes that depends on mono-ubiquitination of histone H2B (H2B-Ub). H3K4 methylation in yeast is catalyzed by Set1, the methyltransferase subunit of COMPASS. We report here the cryo-EM structure of a six-protein core COMPASS subcomplex, which can methylate H3K4 and be stimulated by H2B-Ub, bound to a ubiquitinated nucleosome. Our structure shows that COMPASS spans the face of the nucleosome, recognizing ubiquitin on one face of the nucleosome and methylating H3 on the opposing face. As compared to the structure of the isolated core complex, Set1 undergoes multiple structural rearrangements to cement interactions with the nucleosome and with ubiquitin. The critical Set1 RxR motif adopts a helix that mediates bridging contacts between the nucleosome, ubiquitin and COMPASS. The structure provides a framework for understanding mechanisms of trans-histone cross-talk and the dynamic role of H2B ubiquitination in stimulating histone methylation.

scholarly journals The E3 ubiquitin ligase RAD18 regulates ubiquitylation and chromatin loading of FANCD2 and FANCI

Blood ◽  
2011 ◽  
Vol 117 (19) ◽  
pp. 5078-5087 ◽  
Author(s):  
Stacy A. Williams ◽  
Simonne Longerich ◽  
Patrick Sung ◽  
Cyrus Vaziri ◽  
Gary M. Kupfer
Keyword(s):  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Complementation Group ◽  
Nuclear Antigen ◽  
Core Complex ◽  
Increased Risk ◽  
Interstrand Cross Links ◽  
Cross Links ◽  
Increased Sensitivity ◽  
Proliferating Cell

Abstract Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, congenital abnormalities, and an increased risk for cancer and leukemia. Components of the FA-BRCA pathway are thought to function in the repair of DNA interstrand cross-links. Central to this pathway is the monoubiquitylation and chromatin localization of 2 FA proteins, FA complementation group D2 (FANCD2) and FANCI. In the present study, we show that RAD18 binds FANCD2 and is required for efficient monoubiquitylation and chromatin localization of both FANCD2 and FANCI. Human RAD18-knockout cells display increased sensitivity to mitomycin C and a delay in FANCD2 foci formation compared with their wild-type counterparts. In addition, RAD18-knockout cells display a unique lack of FANCD2 and FANCI localization to chromatin in exponentially growing cells. FANCD2 ubiquitylation is normal in cells containing a ubiquitylation-resistant form of proliferating cell nuclear antigen, and chromatin loading of FA core complex proteins appears normal in RAD18-knockout cells. Mutation of the RING domain of RAD18 ablates the interaction with and chromatin loading of FANCD2. These data suggest a key role for the E3 ligase activity of RAD18 in the recruitment of FANCD2 and FANCI to chromatin and the events leading to their ubiquitylation during S phase.

scholarly journals EZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Boheng Li ◽  
Wee-Joo Chng
Keyword(s):  
Gene Expression ◽  
Essential Role ◽  
Histone H3 ◽  
Epigenetic Silencing ◽  
Post Translational Modifications ◽  
Therapeutic Implications ◽  
Polycomb Repressive Complex 2 ◽  
Lymphoid Malignancies ◽  
Underlying Mechanisms

AbstractEZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which along with other PRC2 components mediates gene expression suppression via the methylation of Histone H3 at lysine 27. Recent studies have revealed a dichotomous role of EZH2 in physiology and in the pathogenesis of cancer. While it plays an essential role in the development of the lymphoid system, its deregulation, whether due to genetic or non-genetic causes, promotes B cell- and T cell-related lymphoma or leukemia. These findings triggered a boom in the development of therapeutic EZH2 inhibitors in recent years. Here, we discuss physiologic and pathogenic function of EZH2 in lymphoid context, various internal causes of EZH2 aberrance and how EZH2 modulates lymphomagenesis through epigenetic silencing, post-translational modifications (PTMs), orchestrating with surrounding tumor micro-environment and associating with RNA or viral partners. We also summarize different strategies to directly inhibit PRC2-EZH2 or to intervene EZH2 upstream signaling.

scholarly journals Chk1-Mediated Phosphorylation of FANCE Is Required for the Fanconi Anemia/BRCA Pathway

2007 ◽  
Vol 27 (8) ◽  
pp. 3098-3108 ◽  
Author(s):  
XiaoZhe Wang ◽  
Richard D. Kennedy ◽  
Kallol Ray ◽  
Patricia Stuckert ◽  
Tom Ellenberger ◽  
...  
Keyword(s):  
Fanconi Anemia ◽  
Mutant Form ◽  
Cross Link ◽  
Core Complex ◽  
Core Enzyme ◽  
Cross Links ◽  
Phase Progression ◽  
Nuclear Foci ◽  
Fancd2 Monoubiquitination

ABSTRACT The eleven Fanconi anemia (FA) proteins cooperate in a novel pathway required for the repair of DNA cross-links. Eight of the FA proteins (A, B, C, E, F, G, L, and M) form a core enzyme complex, required for the monoubiquitination of FANCD2 and the assembly of FANCD2 nuclear foci. Here, we show that, in response to DNA damage, Chk1 directly phosphorylates the FANCE subunit of the FA core complex on two conserved sites (threonine 346 and serine 374). Phosphorylated FANCE assembles in nuclear foci and colocalizes with FANCD2. A nonphosphorylated mutant form of FANCE (FANCE-T346A/S374A), when expressed in a FANCE-deficient cell line, allows FANCD2 monoubiquitination, FANCD2 foci assembly, and normal S-phase progression. However, the mutant FANCE protein fails to complement the mitomycin C hypersensitivity of the transfected cells. Taken together, these results elucidate a novel role of Chk1 in the regulation of the FA/BRCA pathway and in DNA cross-link repair. Chk1-mediated phosphorylation of FANCE is required for a function independent of FANCD2 monoubiquitination.

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