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1.
EMBO J ; 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38886582

ABSTRACT

Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A.

2.
bioRxiv ; 2024 Mar 24.
Article in English | MEDLINE | ID: mdl-38077016

ABSTRACT

Mutational patterns caused by APOBEC3 cytidine deaminase activity are evident throughout human cancer genomes. In particular, the APOBEC3A family member is a potent genotoxin that causes substantial DNA damage in experimental systems and human tumors. However, the mechanisms that ensure genome stability in cells with active APOBEC3A are unknown. Through an unbiased genome-wide screen, we define the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex as essential for cell viability when APOBEC3A is active. We observe an absence of APOBEC3A mutagenesis in human tumors with SMC5/6 dysfunction, consistent with synthetic lethality. Cancer cells depleted of SMC5/6 incur substantial genome damage from APOBEC3A activity during DNA replication. Further, APOBEC3A activity results in replication tract lengthening which is dependent on PrimPol, consistent with re-initiation of DNA synthesis downstream of APOBEC3A-induced lesions. Loss of SMC5/6 abrogates elongated replication tracts and increases DNA breaks upon APOBEC3A activity. Our findings indicate that replication fork lengthening reflects a DNA damage response to APOBEC3A activity that promotes genome stability in an SMC5/6-dependent manner. Therefore, SMC5/6 presents a potential therapeutic vulnerability in tumors with active APOBEC3A.

3.
EMBO Rep ; 22(9): e52145, 2021 09 06.
Article in English | MEDLINE | ID: mdl-34347354

ABSTRACT

The APOBEC3 cytidine deaminases are implicated as the cause of a prevalent somatic mutation pattern found in cancer genomes. The APOBEC3 enzymes act as viral restriction factors by mutating viral genomes. Mutation of the cellular genome is presumed to be an off-target activity of the enzymes, although the regulatory measures for APOBEC3 expression and activity remain undefined. It is therefore difficult to predict circumstances that enable APOBEC3 interaction with cellular DNA that leads to mutagenesis. The APOBEC3A (A3A) enzyme is the most potent deaminase of the family. Using proteomics, we evaluate protein interactors of A3A to identify potential regulators. We find that A3A interacts with the chaperonin-containing TCP-1 (CCT) complex, a cellular machine that assists in protein folding and function. Importantly, depletion of CCT results in A3A-induced DNA damage and cytotoxicity. Evaluation of cancer genomes demonstrates an enrichment of A3A mutational signatures in cancers with silencing mutations in CCT subunit genes. Together, these data suggest that the CCT complex interacts with A3A, and that disruption of CCT function results in increased A3A mutational activity.


Subject(s)
Chaperonin Containing TCP-1 , Cytidine Deaminase , Chaperonin Containing TCP-1/genetics , Cytidine Deaminase/genetics , Mutagenesis , Proteins/genetics
4.
Ground Water ; 50(2): 242-55, 2012.
Article in English | MEDLINE | ID: mdl-21740423

ABSTRACT

Local surface water and stormflow were infiltrated intermittently from a 40-ha basin between September 2003 and September 2007 to determine the feasibility of recharging alluvial aquifers pumped for public supply, near Stockton, California. Infiltration of water produced a pressure response that propagated through unconsolidated alluvial-fan deposits to 125 m below land surface (bls) in 5 d and through deeper, more consolidated alluvial deposits to 194 m bls in 25 d, resulting in increased water levels in nearby monitoring wells. The top of the saturated zone near the basin fluctuates seasonally from depths of about 15 to 20 m. Since the start of recharge, water infiltrated from the basin has reached depths as great as 165 m bls. On the basis of sulfur hexafluoride tracer test data, basin water moved downward through the saturated alluvial deposits until reaching more permeable zones about 110 m bls. Once reaching these permeable zones, water moved rapidly to nearby pumping wells at rates as high as 13 m/d. Flow to wells through highly permeable material was confirmed on the basis of flowmeter logging, and simulated numerically using a two-dimensional radial groundwater flow model. Arsenic concentrations increased slightly as a result of recharge from 2 to 6 µg/L immediately below the basin. Although few water-quality issues were identified during sample collection, high groundwater velocities and short travel times to nearby wells may have implications for groundwater management at this and at other sites in heterogeneous alluvial aquifers.


Subject(s)
Groundwater , Water Movements , Water Supply , California , Models, Theoretical , Time Factors
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