Therapeutic Restriction of the Fanconi Anemia Pathway to Limit Replication-Stress–Driven Genome Catastrophes in Hutchinson–Gilford Progeria Syndrome (HGPS)

Abstract

Hutchinson–Gilford Progeria Syndrome (HGPS) arises from a dominant LMNA mutation that produces progerin, a toxic lamin A variant. Progerin undermines nuclear architecture and perturbs DNA replication, provoking chronic replication stress, micronucleus formation, and persistent DNA damage that drives p53-dependent senescence. Recent mechanistic work shows that the Fanconi anemia (FA) pathway— canonically protective at stalled replication forks— can, under specific conditions, induce large-scale nucleolytic cleavage that primes missegregated chromosomes for chromothripsis. This duality suggests a novel therapeutic approach for HGPS: conditional, transient restriction of FA-dependent nuclease activity at mitosis, preventing catastrophic chromosomal shattering while preserving sufficient fork protection during S phase. This paper synthesizes current cell and mouse evidence, evaluates risks by comparison to Fanconi anemia models, and proposes an experimentally tractable therapeutic strategy with an in-depth in vitro and in vivo testing roadmap.