The Fanconi Anemia Pathway and Fertility

Tsui, Vanessa; Crismani, Wayne

doi:10.1016/j.tig.2018.12.007

Cited by 88 publications

(77 citation statements)

References 112 publications

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“…Fertility defects are a common feature in FA gene knockout female mice, as well as in FA patients (Tsui & Crismani, 2019), which highlights the vital role of FA genes in germ cell development. Until now, besides FANCD1/BRCA2, FAMCM , and FANCU/XRCC2 (Fouquet et al, 2017; Qin et al, 2019; Weinberg‐Shukron et al, 2018; Zhang et al, 2019), novel potential causative mutations in the FANCL gene were also found in the present study.…”

Section: Discussionmentioning

confidence: 99%

FANCL gene mutations in premature ovarian insufficiency

et al. 2020

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884Update of variants iden fi ed in the pancrea c β-cell K ATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes 983 Fundamental role of BMP15 in human ovarian folliculogenesis revealed by null and missense muta ons associated with primary ovarian insuffi ciency Raff aella Rosse , Ilaria Ferrari , Ilaria Beste , Silvia Moleri , Francesco Branca , Luisa Petrone , Palma Finelli and Luca Persani 998 Func onal characteriza on of the fi rst missense variant in CEP78 , a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fer lity 1025 Cri cal assessment of secondary fi ndings in genes linked to primary arrhythmia syndromes Volume 41 , Number 5 was mailed the week of April 06, 2020 Front Cover: The cover image is based on the Research Ar cle FANCL gene muta ons in premature ovarian insuffi ciency by Yajuan Yang et al., h ps://doi.

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Section: Discussionmentioning

confidence: 99%

FANCL gene mutations in premature ovarian insufficiency

et al. 2020

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“…A critical step in the repair of replication forks stalled by ICLs is the biochemical modification of FANCD2 protein by mono-ubiquitination. Genetic deficiency in this pathway leads to Fanconi anemia (FA), characterized by hypersensitivity to DNA crosslinking agents, bone marrow failure, infertility, and cancer predisposition (Garaycoechea and Patel, 2014;Tsui and Crismani, 2019).…”

Section: Introductionmentioning

confidence: 99%

ATR-Mediated FANCI Phosphorylation Regulates Both Ubiquitination and Deubiquitination of FANCD2

Tan

Twest

Murphy

et al. 2020

Front. Cell Dev. Biol.

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DNA interstrand crosslinks (ICLs) are a physical barrier to replication and therefore toxic to cell viability. An important mechanism for the removal of ICLs is the Fanconi Anemia DNA repair pathway, which is initiated by mono-ubiquitination of FANCD2 and its partner protein FANCI. Here, we show that maintenance of FANCD2 and FANCI proteins in a monoubiquitinated form is regulated by the ATR-kinase. Using recombinant proteins in biochemical reconstitution experiments we show that ATR directly phosphorylates FANCI on serine 556, 559, and 565 to stabilize its association with DNA and FANCD2. This increased association with DNA stimulates the conjugation of ubiquitin to both FANCI and FANCD2, but also inhibits ubiquitin deconjugation. Using phosphomimetic and phosphodead mutants of FANCI we show that S559 and S565 are particularly important for protecting the complex from the activity of the deubiquitinating enzyme USP1:UAF1. Our results reveal a major mechanism by which ATR kinase maintains the activation of the FA pathway, by promoting the accumulation of FANCD2 in the ubiquitinated form active in DNA repair.

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“…The first discovered breast cancer predisposition genes, BRCA1 and BRCA2 also turned out to be FANC genes, named FANCS and FANCD1 [ 4 , 5 ]. The ‘FA pathway’ – the assembly of 22 FANC gene products working together in a common process of DNA repair – turns out to be critical for gene editing by CRISPR [ 6 ], the movement of transposases throughout the genome [ 7 , 8 ], crossing over during meiosis [ 9 ], and the resistance of cells to chemotherapy drugs [ 10 , 11 ]. The study of FA has directed many fields of research.…”

Section: Introductionmentioning

confidence: 99%

Structural insight into FANCI–FANCD2 monoubiquitination

Tan

Deans

2020

Essays in Biochemistry

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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.

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The Fanconi Anemia Pathway and Fertility

Cited by 88 publications

References 112 publications

FANCL gene mutations in premature ovarian insufficiency

FANCL gene mutations in premature ovarian insufficiency

ATR-Mediated FANCI Phosphorylation Regulates Both Ubiquitination and Deubiquitination of FANCD2

Structural insight into FANCI–FANCD2 monoubiquitination

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