Research Event

Event participants

Research Event

Event participants

The actin cytoskeleton is extremely dynamic and supports diverse cellular functions in many physiological and pathological processes, including tumorigenesis. However, the mechanisms that regulate the actin-related protein 2/3 (ARP2/3) complex and thereby promote actin polymerization and organization in cancer cells are not well-understood. We previously implicated the proline-rich 11 (PRR11) protein in lung cancer development. In this study, using immunofluorescence staining, actin polymerization assays, and siRNA-mediated gene silencing, we uncovered that cytoplasmic PRR11 is involved in F-actin polymerization and organization. We found that dysregulation of PRR11 expression results in F-actin rearrangement and nuclear instability in non-small cell lung cancer cells. Results from molecular mechanistic experiments indicated that PRR11 associates with and recruits the ARP2/3 complex, facilitates F-actin polymerization, and thereby disrupts the F-actin cytoskeleton, leading to abnormal nuclear lamina assembly and chromatin reorganization. Inhibition of the ARP2/3 complex activity abolished irregular F-actin polymerization, lamina assembly, and chromatin reorganization due to PRR11 overexpression. Notably, experiments with truncated PRR11 variants revealed that PRR11 regulates F-actin through different regions. We found that deletion of either the N or C terminus of PRR11 abrogates its effects on F-actin polymerization and nuclear instability and that deletion of amino acid residues 100–184 or 100–200 strongly induces an F-actin structure called the actin comet tail, not observed with WT PRR11. Our findings indicate that cytoplasmic PRR11 plays an essential role in regulating F-actin assembly and nuclear stability by recruiting the ARP2/3 complex in human non-small cell lung carcinoma cells.

Knowledge of the molecular events in mitochondrial DNA (mtDNA) replication is crucial to understanding the origins of human disorders arising from mitochondrial dysfunction. Twinkle helicase is an essential component of mtDNA replication. Here, we employed atomic force microscopy imaging in air and liquids to visualize ring assembly, DNA binding, and unwinding activity of individual Twinkle hexamers at the single-molecule level. We observed that the Twinkle subunits self-assemble into hexamers and higher-order complexes that can switch between open and closed-ring configurations in the absence of DNA. Our analyses helped visualize Twinkle loading onto and unloading from DNA in an open-ringed configuration. They also revealed that closed-ring conformers bind and unwind several hundred base pairs of duplex DNA at an average rate of ∼240 bp/min. We found that the addition of mitochondrial single-stranded (ss) DNA–binding protein both influences the ways Twinkle loads onto defined DNA substrates and stabilizes the unwound ssDNA product, resulting in a ∼5-fold stimulation of the apparent DNA-unwinding rate. Mitochondrial ssDNA-binding protein also increased the estimated translocation processivity from 1750 to >9000 bp before helicase disassociation, suggesting that more than half of the mitochondrial genome could be unwound by Twinkle during a single DNA-binding event. The strategies used in this work provide a new platform to examine Twinkle disease variants and the core mtDNA replication machinery. They also offer an enhanced framework to investigate molecular mechanisms underlying deletion and depletion of the mitochondrial genome as observed in mitochondrial diseases.

Incorporation of ribonucleotides into DNA can severely diminish genome integrity. However, how ribonucleotides instigate DNA damage is poorly understood. In DNA, they can promote replication stress and genomic instability and have been implicated in several diseases. We report here the impact of the ribonucleotide rATP and of its naturally occurring damaged analog 1,N6-ethenoadenosine (1,N6-ϵrA) on translesion synthesis (TLS), mediated by human DNA polymerase η (hpol η), and on RNase H2–mediated incision. Mass spectral analysis revealed that 1,N6-ϵrA in DNA generates extensive frameshifts during TLS, which can lead to genomic instability. Moreover, steady-state kinetic analysis of the TLS process indicated that deoxypurines (i.e. dATP and dGTP) are inserted predominantly opposite 1,N6-ϵrA. We also show that hpol η acts as a reverse transcriptase in the presence of damaged ribonucleotide 1,N6-ϵrA but has poor RNA primer extension activities. Steady-state kinetic analysis of reverse transcription and RNA primer extension showed that hpol η favors the addition of dATP and dGTP opposite 1,N6-ϵrA. We also found that RNase H2 recognizes 1,N6-ϵrA but has limited incision activity across from this lesion, which can lead to the persistence of this detrimental DNA adduct. We conclude that the damaged and unrepaired ribonucleotide 1,N6-ϵrA in DNA exhibits mutagenic potential and can also alter the reading frame in an mRNA transcript because 1,N6-ϵrA is incompletely incised by RNase H2.

The action mechanisms revealed by the biochemical and structural analyses of replicative and translesion synthesis (TLS) DNA polymerases (Pols) are retained in their cellular roles. In this regard, DNA polymerase θ differs from other Pols in that whereas purified Polθ misincorporates an A opposite 1,N6-ethenodeoxyadenosine (ϵdA) using an abasic-like mode, Polθ performs predominantly error-free TLS in human cells. To test the hypothesis that Polθ adopts a different mechanism for replicating through ϵdA in human cells than in the purified Pol, here we analyze the effects of mutations in the two highly conserved tyrosine residues, Tyr-2387 and Tyr-2391, in the Polθ active site. Our findings that these residues are indispensable for TLS by the purified Pol but are not required in human cells, as well as other findings, provide strong evidence that the Polθ active site is reconfigured in human cells to stabilize ϵdA in the syn conformation for Hoogsteen base pairing with the correct nucleotide. The evidence that a DNA polymerase can configure its active site entirely differently in human cells than in the purified Pol establishes a new paradigm for DNA polymerase function.

With immigration increasingly visible in the news and the political space in the United States and internationally, getting access to accurate, high-quality data is essential to understand immigration’s demographic effects and impacts on the economy, education and labor systems, and communities. This event marks the release of the Immigration Data Matters guide.

What President Trump calls a border crisis is in fact a crisis in the asylum system—one worsened at every turn by his administration’s harsh policies and rhetoric. Rather than spend $5.7 billion on a wall, it would be far more effective to use the money to retool an overwhelmed asylum system, adapt outmatched border enforcement infrastructure to respond to the changing composition of arrivals, and work cooperatively with Mexico to tackle the factors propelling Central Americans to flee.

The House is set to vote on two bills that would largely dismantle the U.S. asylum system at the southern border by significantly narrowing grounds to apply for asylum, eliminating protections for the vast majority of unaccompanied minors, and unilaterally declaring Mexico a safe third country. The result would be a sharp reduction in the number of people permitted to seek humanitarian protection, as this commentary explains.

At this release of an updated version of the popular Immigration Data Matters guide, presenters discuss how to navigate and access the increasing number of data sources on immigration and immigrants in the United States and internationally. 

In its first year, the Trump administration moved to deliver on some of Donald Trump’s campaign promises on immigration, including ramping up enforcement in the U.S. interior and ending the Deferred Action for Childhood Arrivals (DACA) program. The administration also announced the termination of Temporary Protected Status (TPS) for nationals of some countries. This article explores some of the top policy changes.

The Trump administration has significantly cranked up the immigration enforcement machinery in the U.S. interior. Yet even as arrests and deportations are up in the early Trump months, they remain less than half their peaks. This report demonstrates how pushback from California and other "sanctuary" locations makes it quite unlikely that ICE will be able to match record enforcement levels.

Experts on this Spanish language webinar examine the operation of today’s interior immigration enforcement system and how state and local governments, civil society, and consulates are responding.    

Remain in Mexico—the Trump administration policy aimed at deterring the rising numbers of migrants from Central America by requiring them to stay in Mexico through most of their U.S. asylum adjudication process—bears striking similarities to U.S. policy in the 1980s and 1990s that sought to discourage Haitians from making the sea journey to the United States. This article explores the parallels and differences between Remain in Mexico and the earlier narrowing of asylum for Haitians.

During his first 100 days in office, President Trump has taken a sweeping set of actions on immigration, ranging from imposing a travel ban to cutting refugee admissions, "extreme" vetting, and fortifying immigration enforcement at the border and in the U.S. interior. This fact sheet examines the major immigration actions taken to date, legal challenges, and related policy and personnel developments.

A high school diploma has been a core requirement of proposed DREAM Act legislation and the Deferred Action for Childhood Arrivals (DACA) program. Yet a fresh estimate of the number of unauthorized immigrants graduating annually from U.S. high schools has long been missing from the debate. This fact sheet provides up-to-date estimates for the United States and top 15 states, estimating 98,000 such students graduate yearly.

A Spanish language webinar examining the operation of today’s interior enforcement system and how state and local governments, civil society, and consulates are responding.    

Having emerged from a long era of military rule, Myanmar's leaders and many citizens are looking outward. In particular, with Burmese labor migration abroad on the rise, policymakers are examining ways in which to harness remittances as a vehicle for economic development, particularly in impoverished rural areas. This article explores Burmese labor migration flows, financial reforms, and challenges on migration and development.

Governments on the receiving end of migrants and refugees reinforced their commitment to returns in 2017, sending or coercing migrants to move back to impoverished or violent homelands. The Dominican Republic pushed out some 70,000 Haitians and native born of Haitian descent, while more than 500,000 Afghans left Iran and Pakistan. Though many of these migrants chose to return, in practice the line between forced and voluntary returns is blurry.

As the final phase of preparations for the historic adoption of a Global Compact for Safe, Orderly, and Regular Migration approaches, this webinar explores two central objectives of the compact: enhancing the availability and flexibility of pathways for regular migration, and investing in skills development. 

As the final phase of preparations for the historic adoption of a Global Compact for Safe, Orderly, and Regular Migration approaches, this webinar explores two central objectives of the compact: enhancing the availability and flexibility of pathways for regular migration, and investing in skills development.

One of the least developed countries in sub-Saharan Africa, the Democratic Republic of the Congo has experienced significant migration outflows and inflows tied to political and economic crises in recent decades. While most Congolese migrants head to neighboring countries, destinations have diversified, with an uptick in those leaving for opportunities in Europe and beyond. This country profile explores historical and contemporary patterns of migration to and from DR Congo.

Although long one of the world's top migrant destinations, only in the recent past has Germany come to acknowledge and adjust to its role as a country of immigration. Its welcoming approach—a relatively new development—has been put to the test amid massive humanitarian inflows beginning in 2015. This country profile examines Germany's history on immigration and highlights current and emerging debates.

In Brazil, where the majority of colonial-era residents were African slaves and their children, millions of immigrants have joined a conversation about race and identity that continues today. Brazil is home to the largest Japanese population outside of Japan, as well as significant European, Latin American, and Middle Eastern populations. This country profile explores historical and contemporary migration patterns in Brazil.

With nearly 1.4 million internally displaced persons (IDPs), Ukraine is home to one of the largest IDP populations in the world. Five years after Russia's annexation of Crimea, displaced Ukrainians continue to face challenges related to national identity, social cohesion, and political participation. While the Ukrainian government has had some success integrating IDPs, the conflict’s end remains uncertain, and many are unlikely to return to their communities of origin no matter the outcome.

The impact of climate change as a driver of human migration is expected by many to dwarf all others. Still, certain frequently repeated forecasts of the number of people who stand to be displaced by climate change are not informed by a complete understanding of migration dynamics, as this report explains.

Discussion at launch of this MPI-IOM Issue in Brief, Human Rights, Climate Change, Environmental Degradation and Migration: A New Paradigm, which focuses on the vulnerability of environmental migrants and how the international legal framework can better ensure their protection, particularly in the Asia-Pacific region.

This issue brief addresses the rights of migrants whose movement is induced by environmental degradation or climate change, particularly in the highly vulnerable Asia-Pacific region. The brief evaluates the current international legal framework, identifies gaps in the framework and its implementation, and reviews options available to the international community.

This MPI event, in partnership with the International Organization for Migration (IOM), discusses the critical issue of climate-related displacement in the Asia-Pacific region, focusing on the vulnerability of environmental migrants and how the international legal framework can better ensure their protection.

From earthquakes to drought, natural disasters and climate change played a key role in migration flows in 2015. Climate-induced migration surfaced as a concern at the United Nations Climate Change Conference (known as COP21) as international organizations and policymakers have begun to recognize the growing challenges, and potential protection obligations, of such movement.

MPI experts discuss the outcomes from the UN Summit on Large Movements of Refugees and Migrants and President Obama's Leaders Summit on the Global Refugee Crisis and what it means for international cooperation on refugee protection and management of migration flows.

Climate-related displacement is not hypothetical: An average of 21.5 million people per year have been displaced since 2008 by natural disasters, and thousands more have fled slow-onset environmental hazards. While migration can serve as a safety valve to adapt to changing conditions, few orderly, legal channels exist for climate migrants (also known as environmental migrants), as this article explores.

While media and academic discussions of "climate refugees" paint a picture of mass displacement of millions, in reality many communities vulnerable to climate change may choose to stay as a result of strong cultural, historical, and spiritual attachments to place. This article explores this "voluntary immobility" and its implications in the Pacific Islands.

While skilled migration brings widely acknowledged economic benefits for destination countries and migrants, its impact on countries of origin has been the subject of more debate. Despite a growing consensus that origin countries can benefit from emigration and the circulation of skills, enabling this potential to be fully exploited remains a challenge. This report examines initiatives that develop skills and human capital.