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How SUMOylation Fine-Tunes the Fanconi Anemia DNA Repair Pathway.

Coleman KE, Huang TT - Front Genet (2016)

Bottom Line: Fanconi anemia (FA) is a rare human genetic disorder characterized by developmental defects, bone marrow failure and cancer predisposition, primarily due to a deficiency in the repair of DNA interstrand crosslinks (ICLs).SUMOylation is a critical regulator of several DNA repair pathways, however, the role of this modification in controlling the FA pathway is poorly understood.Here, we summarize recent advances in the fine-tuning of the FA pathway by small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligases (STUbLs) and other SUMO-related interactions, and discuss the implications of these findings in the design of novel therapeutics for alleviating FA-associated condition, including cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York NY, USA.

ABSTRACT
Fanconi anemia (FA) is a rare human genetic disorder characterized by developmental defects, bone marrow failure and cancer predisposition, primarily due to a deficiency in the repair of DNA interstrand crosslinks (ICLs). ICL repair through the FA DNA repair pathway is a complicated multi-step process, involving at least 19 FANC proteins and coordination of multiple DNA repair activities, including homologous recombination, nucleotide excision repair and translesion synthesis (TLS). SUMOylation is a critical regulator of several DNA repair pathways, however, the role of this modification in controlling the FA pathway is poorly understood. Here, we summarize recent advances in the fine-tuning of the FA pathway by small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligases (STUbLs) and other SUMO-related interactions, and discuss the implications of these findings in the design of novel therapeutics for alleviating FA-associated condition, including cancer.

No MeSH data available.


Related in: MedlinePlus

The ICL repair pathway. The FANCM-FAAP24 complex first recognizes stalled replication structures, and recruits the FA core complex to the ICL. ATR-Chk1 phosphorylates and activates multiple components, including FANCA, E, I, and D2, which is required for monoubiquitylation of the ID complex by the FA core complex. Upon monoubiquitylation, the activated ID complex localizes to chromatin and coordinates the activities of downstream nucleases that create incisions around the crosslink. The resulting structure is then repaired by multiple processes, involving lesion bypass by TLS polymerases, HR, and NER. Finally, the USP1-UAF1 DUB complex removes monoubiquitin from the ID complex to complete repair. See accompanying text for more details. Yellow spheres indicate Fanconi Anemia-associated proteins (FAAPs) FAAP20, FAAP24, and FAAP100. Targets for SUMOylation highlighted in this review are denoted in green.
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Figure 1: The ICL repair pathway. The FANCM-FAAP24 complex first recognizes stalled replication structures, and recruits the FA core complex to the ICL. ATR-Chk1 phosphorylates and activates multiple components, including FANCA, E, I, and D2, which is required for monoubiquitylation of the ID complex by the FA core complex. Upon monoubiquitylation, the activated ID complex localizes to chromatin and coordinates the activities of downstream nucleases that create incisions around the crosslink. The resulting structure is then repaired by multiple processes, involving lesion bypass by TLS polymerases, HR, and NER. Finally, the USP1-UAF1 DUB complex removes monoubiquitin from the ID complex to complete repair. See accompanying text for more details. Yellow spheres indicate Fanconi Anemia-associated proteins (FAAPs) FAAP20, FAAP24, and FAAP100. Targets for SUMOylation highlighted in this review are denoted in green.

Mentions: Following ID monoubiquitylation, a complex series of steps ensues to complete ICL repair. First, the mono-ubiquitinated ID complex serves as a scaffold for recruitment of several nucleases, which make nucleolytic incisions flanking the ICL to unhook the crosslink. These nucleases include SLX4 (discussed in more detail below), ERCC1-XPF1, and MUS81-EME1 structure-specific endonucleases (Hanada et al., 2006; Knipscheer et al., 2009; Stoepker et al., 2011; Klein Douwel et al., 2014). Cross-linked nucleotides on the complementary strand are subsequently bypassed by the process of TLS, which involves specialized Y-family polymerases such as polζ and REV1 (Räschle et al., 2008; Kim et al., 2012; Budzowska et al., 2015). The nucleolytic incisions result in a double strand break (DSB) in the DNA, which is repaired by HR (discussed below), and nucleotide excision repair (NER) fills the remaining gap (Räschle et al., 2008; Kim and D’Andrea, 2012). Finally, in the last step, the deubiquitinating (DUB) complex USP1-UAF1 removes monoubiquitin from the ID complex, allowing for pathway regeneration (Nijman et al., 2005; Cohn et al., 2007) (Figure 1). For more extensive reviews on the steps of the FA pathway, please refer to the following reviews: (Kim and D’Andrea, 2012; Walden and Deans, 2014; Duxin and Walter, 2015). Despite extensive study, it is likely that additional aspects of FA pathway activation and regulation remain unidentified, prompting recent studies of other regulatory proteins and post-translational modifications (PTMs) involved in the FA pathway.


How SUMOylation Fine-Tunes the Fanconi Anemia DNA Repair Pathway.

Coleman KE, Huang TT - Front Genet (2016)

The ICL repair pathway. The FANCM-FAAP24 complex first recognizes stalled replication structures, and recruits the FA core complex to the ICL. ATR-Chk1 phosphorylates and activates multiple components, including FANCA, E, I, and D2, which is required for monoubiquitylation of the ID complex by the FA core complex. Upon monoubiquitylation, the activated ID complex localizes to chromatin and coordinates the activities of downstream nucleases that create incisions around the crosslink. The resulting structure is then repaired by multiple processes, involving lesion bypass by TLS polymerases, HR, and NER. Finally, the USP1-UAF1 DUB complex removes monoubiquitin from the ID complex to complete repair. See accompanying text for more details. Yellow spheres indicate Fanconi Anemia-associated proteins (FAAPs) FAAP20, FAAP24, and FAAP100. Targets for SUMOylation highlighted in this review are denoted in green.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4835495&req=5

Figure 1: The ICL repair pathway. The FANCM-FAAP24 complex first recognizes stalled replication structures, and recruits the FA core complex to the ICL. ATR-Chk1 phosphorylates and activates multiple components, including FANCA, E, I, and D2, which is required for monoubiquitylation of the ID complex by the FA core complex. Upon monoubiquitylation, the activated ID complex localizes to chromatin and coordinates the activities of downstream nucleases that create incisions around the crosslink. The resulting structure is then repaired by multiple processes, involving lesion bypass by TLS polymerases, HR, and NER. Finally, the USP1-UAF1 DUB complex removes monoubiquitin from the ID complex to complete repair. See accompanying text for more details. Yellow spheres indicate Fanconi Anemia-associated proteins (FAAPs) FAAP20, FAAP24, and FAAP100. Targets for SUMOylation highlighted in this review are denoted in green.
Mentions: Following ID monoubiquitylation, a complex series of steps ensues to complete ICL repair. First, the mono-ubiquitinated ID complex serves as a scaffold for recruitment of several nucleases, which make nucleolytic incisions flanking the ICL to unhook the crosslink. These nucleases include SLX4 (discussed in more detail below), ERCC1-XPF1, and MUS81-EME1 structure-specific endonucleases (Hanada et al., 2006; Knipscheer et al., 2009; Stoepker et al., 2011; Klein Douwel et al., 2014). Cross-linked nucleotides on the complementary strand are subsequently bypassed by the process of TLS, which involves specialized Y-family polymerases such as polζ and REV1 (Räschle et al., 2008; Kim et al., 2012; Budzowska et al., 2015). The nucleolytic incisions result in a double strand break (DSB) in the DNA, which is repaired by HR (discussed below), and nucleotide excision repair (NER) fills the remaining gap (Räschle et al., 2008; Kim and D’Andrea, 2012). Finally, in the last step, the deubiquitinating (DUB) complex USP1-UAF1 removes monoubiquitin from the ID complex, allowing for pathway regeneration (Nijman et al., 2005; Cohn et al., 2007) (Figure 1). For more extensive reviews on the steps of the FA pathway, please refer to the following reviews: (Kim and D’Andrea, 2012; Walden and Deans, 2014; Duxin and Walter, 2015). Despite extensive study, it is likely that additional aspects of FA pathway activation and regulation remain unidentified, prompting recent studies of other regulatory proteins and post-translational modifications (PTMs) involved in the FA pathway.

Bottom Line: Fanconi anemia (FA) is a rare human genetic disorder characterized by developmental defects, bone marrow failure and cancer predisposition, primarily due to a deficiency in the repair of DNA interstrand crosslinks (ICLs).SUMOylation is a critical regulator of several DNA repair pathways, however, the role of this modification in controlling the FA pathway is poorly understood.Here, we summarize recent advances in the fine-tuning of the FA pathway by small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligases (STUbLs) and other SUMO-related interactions, and discuss the implications of these findings in the design of novel therapeutics for alleviating FA-associated condition, including cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York NY, USA.

ABSTRACT
Fanconi anemia (FA) is a rare human genetic disorder characterized by developmental defects, bone marrow failure and cancer predisposition, primarily due to a deficiency in the repair of DNA interstrand crosslinks (ICLs). ICL repair through the FA DNA repair pathway is a complicated multi-step process, involving at least 19 FANC proteins and coordination of multiple DNA repair activities, including homologous recombination, nucleotide excision repair and translesion synthesis (TLS). SUMOylation is a critical regulator of several DNA repair pathways, however, the role of this modification in controlling the FA pathway is poorly understood. Here, we summarize recent advances in the fine-tuning of the FA pathway by small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligases (STUbLs) and other SUMO-related interactions, and discuss the implications of these findings in the design of novel therapeutics for alleviating FA-associated condition, including cancer.

No MeSH data available.


Related in: MedlinePlus