Cisplatin Depletes TREX2 and Causes Robertsonian Translocations as Seen in TREX2 Knockout Cells

Chen, Ming Jiu; Dumitrache, Lavinia C.; Wangsa, Danny; Mei, Sheng; Padilla‐Nash, Hesed; Ried, Thomas; Hasty, Paul

doi:10.1158/0008-5472.can-07-1146

Cited by 18 publications

(41 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another group has previously reported the reduced proliferation and presence of Robertsonian translocations, duplications, and deletions in two clones of Trex2-deficient ES cells (27). Surprisingly, we did not detect any chromosomal abnormalities in more than one hundred metaphases analyzed by SKY from MEFs and keratinocytes isolated from at least four knockout and wt Trex2 mice (Supplementary Fig.…”

Section: Generation Of Trex2mentioning

confidence: 55%

“…However, these animals do show increased tumorigenic susceptibility when exposed to carcinogens. Previous studies in ES cells lacking Trex2 have shown that TREX2 is required for efficient proliferation and chromosomal stability (20,27). Severe chromosomal instability is usually associated with lethality, growth retardation, premature aging, immunologic abnormalities, or cancer (33).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, the DNA-PK knockout mouse, which is predisposed to chromosomal instability, shows a decreased susceptibility to DMBA-induced tumorigenesis due to the preexisting DNA damage in these cells (39). The chromosomal instability observed in the two TREX2-deficient ES clones (27) could be a consequence of replication stress generated during ES growth and selection. Therefore, our data indicate that TREX2 suppression does not lead to a general chromosomal instability, at least in the absence of genotoxic stress.…”

Section: Discussionmentioning

confidence: 99%

“…Otherwise, TREX2 seems to be important for chromosomal stability. As such, TREX2 deletion in embryonic stem (ES) causes high levels of Robertsonian Translocations (27), but this effect is independent of its exonuclease activity and DNA binding domains (28). The biochemical activities and the mechanisms by which TREX2 prevents chromosomal instability and the consequences of TREX2 deficiency in the organism remain unknown.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Increased Susceptibility to Skin Carcinogenesis in TREX2 Knockout Mice

et al. 2009

View full text Add to dashboard Cite

TREX2 is a proofreading 3 ¶-5 ¶ exonuclease that can be involved in genome maintenance; however, its biological role remains undefined. To better understand the function and physiologic relevance of TREX2, we generated mice deficient in TREX2 by targeted disruption of its unique coding exon. The knockout mice are viable and do not show relevant differences in growth, survival, lymphocyte development, or spontaneous tumor incidence compared with their wild-type counterparts over a period of up to 2 years. Also, we did not observe chromosomal instability or defects in cell proliferation and cell cycle upon loss of TREX2. We have observed that TREX2 expression is not ubiquitous, being expressed preferentially in tissues with stratified squamous epithelia, such as the skin or esophagus, and specifically in keratinocytes. Interestingly, TREX2-null mice are more susceptible to skin carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA) compared with wild-type mice. This phenotype correlates with a reduction of DMBA-induced apoptosis in both the epidermis and keratinocytes of TREX2-null mice. Altogether, our results suggest a tumor suppressor role for TREX2 in skin carcinogenesis through which it contributes to keratinocyte apoptosis under conditions of genotoxic stress. [Cancer Res 2009;69(16):6676-84]

show abstract

Section: Generation Of Trex2mentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Increased Susceptibility to Skin Carcinogenesis in TREX2 Knockout Mice

et al. 2009

View full text Add to dashboard Cite

show abstract

“…There is some genetic evidence for extrinsic proofreading by some exonucleases of DNA polymerases (35)(36)(37), but evidence that the TREX enzymes act as proofreaders is supported only by in vitro studies (1). Although direct genetic evidence for a TREX2 role in mammalian DNA maintenance is lacking, cells deleted of TREX2 exhibit increased levels of chromosomal rearrangements suggesting a role in genome stability (38). The severe consequences of 3Ј-deoxyribonuclease loss of function in cells highlight the need to understand the precise mechanisms of these exonucleases in DNA metabolic processes.…”

mentioning

confidence: 99%

Cooperative DNA Binding and Communication across the Dimer Interface in the TREX2 3′ → 5′-Exonuclease

Perrino

Silva

Harvey

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

The activity of human TREX2-catalyzed 3 3 5-deoxyribonuclease has been analyzed in steady-state and single turnover kinetic assays and in equilibrium DNA binding studies. These kinetic data provide evidence for cooperative DNA binding within TREX2 and for coordinated catalysis between the TREX2 active sites supporting a model for communication between the protomers of a TREX2 dimer. Mobile loops positioned adjacent to the active sites provide the major DNA binding contribution and facilitate subsequent binding into the active sites. Mutations of three arginine residues on these loops cause decreased TREX2 activities by up to 60-fold. Steady-state kinetic assays of these arginine to alanine TREX2 variants result in increased K m values for DNA substrate with no effect on k cat values indicating contributions exclusively to DNA binding by all three of the loop arginines. TREX2 heterodimers were prepared to determine whether exonuclease activity in one protomer is communicated to the opposing protomer. Evidence for communication across the dimer interface is provided by the 7-fold lower catalytic activity measured in the TREX2 WT/H188A heterodimer compared with the TREX2 WT homodimer, contrasting the 2-fold lower activity measured in the TREX2 WT/R163A,R165A,R167A heterodimer. The measured activity in TREX2WT/H188A heterodimer indicates that defective catalysis in one protomer reduces activity in the opposing protomer. A DNA binding analysis of TREX2 and the heterodimers indicates a cooperative binding effect within the TREX2 protomer. Finally, single turnover kinetic assays identify DNA binding as the rate-limiting step in TREX2 catalysis.The 3Ј 3 5Ј-deoxyribonucleases play fundamental roles in a variety of DNA metabolic pathways. These enzymes process DNA 3Ј ends by removing nucleotides one at a time to remodel 3Ј termini for subsequent molecular events in cells (1, 2). TREX1 is the most active 3Ј-deoxyribonuclease purified from mammalian cells (3, 4). TREX2 has not been purified from cells, but recombinant TREX1 and TREX2 generated in Escherichia coli confirm the robust nature of these deoxyribonucleases with TREX1 exhibiting about a 10-fold greater activity than TREX2(5-7). The high catalytic efficiencies measured for TREX1 and TREX2 can be attributed in part to the nature of the active sites. The TREX gene sequences and Mg 2ϩ ion dependence suggested that these deoxyribonucleases might be members of the DnaQ-like exonuclease family that utilize a two Mg 2ϩ ion-dependent mechanism for catalysis (8 -12). The DnaQ-like family contains both deoxyribo-and riboexonucleases and has been divided into two subfamilies characterized by the presence of four conserved carboxylate residues and a histidine (DEDD-h) or a tyrosine (DEDD-y) positioned in the active site (13). The TREX enzymes prefer excision of deoxynucleotide polymers over ribonucleotide polymers by about 1000-fold (5) 2 with specificity for unmodified 3Ј termini (14, 15). The four carboxylate residue side chains in the DnaQ-like enzymes coordinate two divalen...

show abstract