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Telomere healing following DNA polymerase arrest‐induced breakages is likely the main mechanism generating chromosome 4p terminal deletions
Author(s) -
Hannes Femke,
Houdt Jeroen Van,
Quarrell Oliver W.,
Poot Martin,
Hochstenbach Ron,
Fryns JeanPierre,
Vermeesch Joris R.
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21368
Subject(s) - telomere , biology , genetics , telomerase , chromosome , dna replication , chromosomal translocation , dna , gene
Abstract Constitutional developmental disorders are frequently caused by terminal chromosomal deletions. The mechanisms and/or architectural features that might underlie those chromosome breakages remain largely unexplored. Because telomeres are the vital DNA protein complexes stabilizing linear chromosomes against chromosome degradation, fusion, and incomplete replication, those terminal‐deleted chromosomes acquired new telomeres either by telomere healing or by telomere capture. To unravel the mechanisms leading to chromosomal breakage and healing, we sequenced nine chromosome 4p terminal deletion boundaries. A computational analysis of the breakpoint flanking region, including 12 previously published pure terminal breakage sites, was performed in order to identify architectural features that might be involved in this process. All terminal 4p truncations were likely stabilized by telomerase‐mediated telomere healing. In the majority of breakpoints multiple genetic elements have a potential to induce secondary structures and an enrichment in replication stalling site motifs were identified. These findings suggest DNA replication stalling‐induced chromosome breakage during early development is the first mechanistic step leading toward terminal deletion syndromes. Hum Mutat 31:1–9, 2010. © 2010 Wiley‐Liss, Inc.