Holliday junction 5′ flap endonuclease GEN1 (GEN1)

Holliday junction 5′ flap endonuclease GEN1 (GEN1) is a member of the Rad2/XPG nuclease family that acts as a structure-selective endonuclease specialized for resolving Holliday junctions, which are critical four-way DNA intermediates formed during homologous recombination and double-strand break repair[1][2][3][5][6]. GEN1 accomplishes this by specific dual incisions across the junction to generate ligatable nicked duplex DNA[1][2][3]. Biochemical and structural analyses reveal that GEN1 can dimerize on DNA junctions, allowing for symmetrical cleavage, and it possesses a unique chromodomain for efficient DNA recognition not present in other Rad2/XPG nucleases[6][7]. GEN1’s activity is essential for genome integrity, proper chromosome segregation, and the final resolution of recombination structures before cell division[1][3][5]. GEN1 is functionally redundant with the MUS81-EME1 complex, and deficiency of both partners leads to synthetic lethality and increased genome instability in mammalian systems, highlighting its importance in DNA repair[5]. Although not an established clinical drug target, disruption or modulation of GEN1 function may impact cancer therapies that depend on DNA damage and genomic instability[5].

Other names

Flap endonuclease GEN homolog 1GEN1FLJ40869GenHolliday junction resolvaseGen endonuclease homolog 1

Endonucleolytic cleavage of DNA at Holliday junctions to resolve recombination intermediates[1][2][3] Indirectly, agents targeting DNA repair pathways or inducing DNA damage may modulate GEN1 activity as an endogenous repair factor[5]