title: Pericentromeric regions are refractory to prompt repair after replication stress-induced breakage in HPV16 E6E7-expressing epithelial cells.
abstract: Chromosomal instability is the major form of genomic instability in cancer cells. Amongst various forms of chromosomal instability, pericentromeric or centromeric instability remains particularly poorly understood. In the present study, we found that pericentromeric instability, evidenced by dynamic formation of pericentromeric or centromeric rearrangements, breaks, deletions or iso-chromosomes, was a general phenomenon in human cells immortalized by expression of human papillomavirus type 16 E6 and E7 (HPV16 E6E7). In particular, for the first time, we surprisingly found a dramatic increase in the proportion of pericentromeric chromosomal aberrations relative to total aberrations in HPV16 E6E7-expressing cells 72 h after release from aphidicolin (APH)-induced replication stress, with pericentromeric chromosomal aberrations becoming the predominant type of structural aberrations (~70% of total aberrations). In contrast, pericentromeric aberrations accounted for only about 20% of total aberrations in cells at the end of APH treatment. This increase in relative proportion of pericentromeric aberrations after release from APH treatment revealed that pericentromeric breaks induced by replication stress are refractory to prompt repair in HPV16 E6E7-expressing epithelial cells. Telomerase-immortalized epithelial cells without HPV16 E6E7 expression did not exhibit such preferential pericentromeric instability after release from APH treatment. Cancer development is often associated with replication stress. Since HPV16 E6 and E7 inactivate p53 and Rb, and p53 and Rb pathway defects are common in cancer, our finding that pericentromeric regions are refractory to prompt repair after replication stress-induced breakage in HPV16 E6E7-expressing cells may shed light on mechanism of general pericentromeric instability in cancer.
authors.affiliation: Department of Anatomy, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Deng
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.forename: Annie L M
authors.initials: AL
authors.lastname: Cheung
mesh_terms: D016590:Aphidicolin / Q000494:pharmacology; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D002461:Cell Line, Transformed; D002503:Centromere / Q000235:genetics*; D043171:Chromosomal Instability / Q000187:drug effects / Q000235:genetics; D002869:Chromosome Aberrations / Q000187:drug effects; D019457:Chromosome Breakage / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D018613:Microscopy, Confocal; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D032681:Spectral Karyotyping; D019098:Telomerase / Q000235:genetics / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C068651:E6 protein, Human papillomavirus type 16; C468783:H2AX protein, human; D006657:Histones; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D016590:Aphidicolin; D019098:Telomerase