New Insights into the Roles of FAN1 Nuclease in Genome Maintenance and Disease
type: CreativeWork
description: Exogenous and endogenous insults to genomic integrity are an existential threat to every species, and therefore robust DNA damage repair mechanisms have evolved to protect against genotoxic threats. FANCD2 and FANCI associated nuclease 1 (FAN1) has roles in protection against two major threats to genomic stability: DNA interstrand crosslinks (ICLs), and the expansion of trinucleotide repeats. ICLs are highly deleterious lesions that disrupt replication, are destructive to dividing cells, and are extremely toxic to the hematopoietic system. The replication-dependent Fanconi anemia (FA) pathway defends against ICL toxicity in rapidly dividing cells. However, while it is critical for protecting the bone marrow, the FA pathway is ineffective in the less-proliferative tissues of the kidney and liver. FAN1 interacts with FA pathway proteins and has been shown to process ICLs in biochemical studies. Depletion of FAN1 sensitizes cells to ICL-inducing agents in vitro, but does not cause bone marrow failure in vivo. Rather, it leads to a hereditable chronic kidney disease called karyomegalic interstitial nephritis (KIN), characterized by widespread karyomegaly, end stage renal disease, and liver dysfunction, suggesting FAN1 may play an important genoprotective role in the kidney and liver. Yet a complete picture of the role of FAN1 in DNA damage repair has been hampered by potential compensatory activity of other nucleases in the setting of FAN1 deficiency. The Smogorzewska laboratory has previously shown evidence of redundancy between FAN1 and the nuclease SNM1A/DCLRE1A, which has also been shown to process ICLs. Here, I describe a synergistic ICL repair deficiency phenotype in mouse embryonic fibroblasts derived from Fan1−/− Snm1a−/− (dKO) mice, which exceeds that of FA pathway-deficient cells. In vivo, dKO mice exhibit profound karyomegaly in the kidney and liver. However, the mice exhibit no spontaneous bone marrow deficiency. Even when the hematopoietic system is chronic…
abstract: Exogenous and endogenous insults to genomic integrity are an existential threat to every species, and therefore robust DNA damage repair mechanisms have evolved to protect against genotoxic threats. FANCD2 and FANCI associated nuclease 1 (FAN1) has roles in protection against two major threats to genomic stability: DNA interstrand crosslinks (ICLs), and the expansion of trinucleotide repeats. ICLs are highly deleterious lesions that disrupt replication, are destructive to dividing cells, and are extremely toxic to the hematopoietic system. The replication-dependent Fanconi anemia (FA) pathway defends against ICL toxicity in rapidly dividing cells. However, while it is critical for protecting the bone marrow, the FA pathway is ineffective in the less-proliferative tissues of the kidney and liver. FAN1 interacts with FA pathway proteins and has been shown to process ICLs in biochemical studies. Depletion of FAN1 sensitizes cells to ICL-inducing agents in vitro, but does not cause bone marrow failure in vivo. Rather, it leads to a hereditable chronic kidney disease called karyomegalic interstitial nephritis (KIN), characterized by widespread karyomegaly, end stage renal disease, and liver dysfunction, suggesting FAN1 may play an important genoprotective role in the kidney and liver. Yet a complete picture of the role of FAN1 in DNA damage repair has been hampered by potential compensatory activity of other nucleases in the setting of FAN1 deficiency. The Smogorzewska laboratory has previously shown evidence of redundancy between FAN1 and the nuclease SNM1A/DCLRE1A, which has also been shown to process ICLs. Here, I describe a synergistic ICL repair deficiency phenotype in mouse embryonic fibroblasts derived from Fan1−/− Snm1a−/− (dKO) mice, which exceeds that of FA pathway-deficient cells. In vivo, dKO mice exhibit profound karyomegaly in the kidney and liver. However, the mice exhibit no spontaneous bone marrow deficiency. Even when the hematopoietic system is chronic…
author: Saffran, Christian S
keywords: FAN1, DNA interstrand crosslink repair, karyomegalic interstitial nephritis (KIN), SNM1A redundancy, Huntington's disease, MIP-box–MLH1 interaction, Life Sciences
date published: 2023-01-01T08:00:00Z
date modified: 2026-07-24T04:11:51Z
provider: Rockefeller
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Rockefeller