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Chromosome organization is increasingly recognized as an active regulator of DNA recombination. In particular, cohesin-mediated loop extrusion can bring distant chromosomal regions into proximity and thereby facilitate long-range DNA search. This principle is illustrated in two distinct recombination systems: V(D)J recombination in developing mouse B cells and homologous repair of DNA double-strand breaks in budding yeast. During immunoglobulin heavy-chain (Igh) V(D)J recombination, RAG endonuclease initiates recombination at the D-J_H recombination center and scans upstream chromatin brought into proximity through cohesin-mediated loop extrusion. Large-scale inversion of the 2.4-Mb V_H locus and manipulation of the cohesin-releasing factor WAPL revealed that physiological Igh locus contraction is mediated by enhanced loop extrusion, enabling RAG to scan across the extended V_H region while overcoming CTCF-dependent barriers. These findings establish loop extrusion as a key mechanism coupling chromosome contraction to long-range antigen-receptor gene assembly.

A related role for loop extrusion is observed during homologous repair of DNA double-strand breaks in Saccharomyces cerevisiae. Deletion of the cohesin-releasing factor Wpl1, a genetic perturbation associated with enhanced loop extrusion, selectively promotes repair using intrachromosomal but not interchromosomal donors. This effect requires cohesin but is independent of sister chromatid cohesion and depends on the DNA damage response kinase Mec1. Moreover, swapping the locations of the centromere-distal DSB and the centromeric donor abolished the wpl1∆-mediated repair enhancement, suggesting that a donor-proximal centromeric barrier may facilitate homologous repair by constraining loop extrusion and stabilizing local chromatin contacts. Together, these studies reveal a shared functional principle by which cohesin-mediated loop extrusion facilitates long-range DNA search, while highlighting how the positioning of loop-extrusion barriers can shape the efficiency and specificity of recombination.