Fanconi anemia FAN CD2 and FAN CI proteins regulate the nuclear dynamics of splicing factors

Abstract

Proteins disabled in the cancer-prone disorder Fanconi anemia (FA) ensure the maintenance of chromosomal stability during DNA replication. FA proteins regulate replication dynamics, coordinate replication-coupled repair of interstrand DNA cross-links, and mitigate conflicts between replication and transcription. Here we show that FAN CI and FAN CD2 associate with splicing factor 3B1 (SF3B1), a key spliceosomal protein of the U2 small nuclear ribonucleoprotein (U2 snRNP). FAN CI is in close proximity to SF3B1 in the nucleoplasm of interphase and mitotic cells. Furthermore, we find that DNA replication stress induces the release of SF3B1 from nuclear speckles in a manner that depends on FAN CI and on the activity of the checkpoint kinase ATR. In chromatin, both FAN CD2 and FAN CI associate with SF3B1, prevent accumulation of postcatalytic intron lariats, and contribute to the timely eviction of splicing factors. We propose that FAN CD2 and FAN CI contribute to the organization of functional domains in chromatin, ensuring the coordination of DNA replication and cotranscriptional processes.